Spiroannulation reaction

Total Synthesis via Oxidative Spiroannulation Reactions of Phenol Derivatives with PI DA or PI FA... 

Iodine(III)-induced spiroannulation reactions of phenol derivatives have been applied widely to total syntheses of related natural products. These reactions have been usually carried out in MeCN, but recently polyfluorinated alcohols such as CF3CH2OH and (CF3)2CHOH are prefered. 

A facile synthesis of the known antifungal antibiotic ( )-geodin (29) corresponding to the spirocoumaranone part of Sch 202596 (149) was achieved by PIFA-induced spiroannulation reaction of the phenol (148) [105] (Scheme 19). 

Several efficient methods for PIFA-induced spiroannulation reactions of sily-lated phenol derivatives [44] or phenols [45] toward total synthesis of dis-corhabdin alkaloids having potent cytotoxicities and unique structures have been developed by Kita and co-workers. Utilizing these methodologies, total syntheses of discorhabdin C (30) [106] and discorhabdin A (31) [107] have been accomplished (Scheme 20,21). 

Ley and co-workers applied the polymer-supported hypervalent iodine reagents, poly(diacetoxyiodo)styrene (PDAIS) or polybis(trifluoroacetoxyio-do)styrene (PBTIS) to the above-mentioned spiroannulation reaction. They succeeded in the concise syntheses of ( )-oxomaritidine (40) and ( )-epimari-tidine (41) using this methodology as the key steps [116] (Scheme 26). 

Honda and co-workers applied the above procedure to the formal total synthesis of enantiopure (-)-TAN1251A (45b), a muscarinic receptor antagonist, isolated from a culture of Penicillium thomii RA-89 [121]. The best yield of the spiroannulation reaction of the phenol 156 using PIDA was achieved by the reaction in (CF3)2CHOH similar to the Sorensen s procedure [119]. Incidentally, none of the desired product was obtained by the typical stepwise procedure using chlorination with NCS followed by Ag20 oxidation (Scheme 29). 

An oxidative spiroannulation reaction was carried out for simple phenols and as a result good yields of spiro-compounds containing tetrahydrofuran rings were obtained <02TL3597>. In the stereospecific and enantiospecific total synthesis of the sarpagine indole alkaloid dehydro-16-epinormacusine B, an oxidative cyclization of the alcohol shown below was the key and final step <02OL4681>. 

For example, a variety of natural products bearing spirocyclic systems exist, and many of them are biosynthetically formed by oxidative spiroannulation processes. Hypervalent iodine(III) reagents are thus considered as one of the most effective oxidants for these oxidation processes. Several efficient methods for PIFA-induced spiroannulation reactions of phenols [48, 49] towards the total synthesis of discorhabdin alkaloids [50, 51] and their oxa-analogues have been published [52, 53], which were accomplished via hypervalent iodine oxidation of phenols or (9-trimethylsilylated phenol derivatives to the azacarbocyclic spirodienones as a key step (Scheme 8). 

As can be seen below, another route for the preparation of spiroannulated 1,3-dihydrobenzo[c]furans (vide supra) was reported by Hotha, who made use of an AuCl, promoted intramolecular Diels-Alder reaction <06TL3307>. 

At this time, we can focus on the creation of the butenolide. Sulfur based methodoly allows simplification to the simple butanolide as in 170. While cyclobutanone spiroannulation of 171 followed by a Baeyer-Villiger reaction would create 170,... 

Better yields of cyclobutanones were obtained with steroidal ketones.85 86 In the reaction of 5a-cholestan-3-one (5) with diazocyclopropane, spiroannulation to give 6 (30%) dominated insertion to give 7 (24%), and with 3/ -acetoxy-5a-pregnane-l 1,20-dione (8) only spiroannulation to give 9 (60%) was observed.85 A comparable high yield (78%) of a spiroannulation product 11 was obtained with trispiro[2.0.2.0.2.1]decan-10-one (10).84 It is apparent that efficient formation of oxaspiropentanes as direct precursors of cyclobutanones only takes place with sterically hindered ketones. 

Phenyl(propynyl)iodonium tetrafluoroborate reacts with potassium 2-phenyl-1,3-indandionate in tetrahydrofuran to give the alkynyl and spiroannulated indandiones shown in equation 265. With sodium 2-ethyl-1,3-indandionate in terf-butyl alcohol, a vinyl ether is produced (equation 266). These observations are relevant to the general comments in section II.D.7 concerning the fate of 26 and related alkylidenecarbenes in reactions of [5 + OJenolates with alkyliodonium ions containing short (< three carbons) alkyl chains. 

Metal-based reagents are often used to promote one- and two-electron oxidations of arenols. Radical-mediated C-0 coupling reactions of aryloxy radicals can, of course, lead to ortho-quinol derivatives, but the preparative value of such an approach is poor and essentially limited to intramolecular cases. For example, certain bis-phenols such as 36a-c have been spiroannulated in good yields by diradical C-0 coupling under favorable one-electron oxidation regimes (Figure 12) [65-67]. 

When furans were tethered at the 2-position to silyl enol ethers, an electrochemical spiroannulation occurred at the 2-position, as exemplified in Equation (23) <2006CC194>. This reaction pathway is a manifestation of the higher nucleophilicity of the furan C-2 position, resulting in the isolation of the kinetic products. 

Allylic alcohols can serve as 7t-allyl cation precursors to act as electrophiles in Sn reactions with a tethered O-nucleophile giving rise to the formation of spiroannulated tetrahydrofurans <2000TL3411>. Michael acceptors are also suitable electrophiles for the cyclization to tetrahydrofuran rings <2003T1613>. The Tsuji-Trost allylation has found widespread application in the synthesis of carbo- and heterocyclic compounds. Allylic substitution has been employed in the stereoselective synthesis of 2-vinyl-5-substituted tetrahydrofurans <2001H(54)419>. A formal total synthesis of uvaricin makes twofold use of the Tsuji-Trost reaction in a double cyclization to bis-tetrahydrofurans (Equation 73) <20010L1953>. 

It should be noted that several domino reactions exist where the Michael/SN-type processes are reversed. For instance, bicylo[3.3.1]nonane ring systems, applicable as synthons for the construction of various natural products [96], have been synthesized by Srikrishna and coworkers using a domino SN/Michael process [97]. This type of domino reaction was also used by the group of Bunce to synthesize N-pro-tected pyrrolidines and piperidines bearing functionalized side chains at C-2 [98], For a domino alkylation/spiroannulation process to give homoerythrina alkaloids 2-177 [99], Desmaele/dAngelo and coworkers have treated the 2-tetralones 2-179 with 2-180 in the presence of Cs2C03 as base (Scheme 2.42) [100],... 

The spiroannulation approach described in Scheme 1 has been easily extended to analogous 1,2-dimethylenecycloalkanes. A wide variety of spirocycles have been synthesized from the reactions of magnesium complexes of 1,2-dimethylenecyclopentane and 1,2-dimethylenecycloheptane with l,n-dibromoalkanes and are shown in Table 1. Therefore, the present spiroannulation method provides a very general approach to a large number of spirocarbocycles with different combinations of ring sizes. 

Altenbach used the Michael addition of sodium methyl malonate to allene (206) for a dia-stereoselective spiroannulation to a steroid (equation 72). Or, in imaginative work by Okamura, allenyl sulfoxides were transformed into enantiomerically pure hydrocarbons by pericyclic reactions like electrocyclic ring closure (equation 73) or intramolecular cycloaddition (equation 74). Note that the starting materials (propargylic alcohols) are readily accessible as single enantiomers. 

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