Spiro Isomers

The tricyclic spiro system having one methyl group was also examined (Fig. 6) (24, 25). This system can give the four isomers 23, 24, 26, and 27. The isomers 23 and 24 come from the cyclization of dihydroxyketone 22 whereas the isomers 26 and 27 come from the cyclization of the isomeric dihydroxyketone 25. In this case, 22 and 25 are not interconvertible under acidic conditions. Each spiro isomer can exist in two different conformations. The theoretical analysis, however, predicted that isomer 23 exists as a mixture of conformers 23A (0.5 kcal/mol) and 23B (0 kcal/mol) whereas isomer 24 exists in the conformation 24A (0 kcal/mol) (Fig. 6). Approximately, a 1 1 mixture of isomers 23 and 24 should therefore be isolated from the cyclization of dihydroxyketone 22. 

While a full discussion of synthetic approaches toward this family is beyond the scope of this chapter, the fused /3-lactone is invariably introduced via dehydration of a hydroxy acid (see Section 2.06.9.6 and Equation 38) <2006JOC1220>. Dehydration is most commonly achieved with BOP-C1, although Ph3PCl2 has also been used <2005OL2699>. The fused /3-lactone can be installed in the presence of the exocyclic alcohol, suggesting that the fused lactone may be more stable than the spiro isomer <2006JOC1220, 2006OBC2845>. 

Tominaga and coworkers [82,83] reported a thiirane synthesis starting from 2-mercapto-l,3-thiazole derivative 180 bearing a trimethylsilyl group (Scheme 56). Treatment of 180 with CsF in acetonitrile and then with an aldehyde provided adducts 182 that fragmented via the spiro-isomer 183. Interestingly, the use of TASF as the fluorine anion source provided alcohols 185. The latter products were slowly transformed into the respective thiiranes 184 and thiazolidinone on storage (Table 9). 

A novel rearrangement of suitably 2-substituted side-chain perhy-dro-isoxazolo[2,3-a]pyridines has been shown to afford indolizine and quinolizine derivatives (86TL1727). Thus, 2-spirocyclopropylperhydro-isoxazolo[2,3-a]pyridine (61), obtained as a mixture with the 3-spiro isomer from the reaction between 3,4,5,6-tetrahydropyridine-l-oxide and methylene cyclopropane, undergoes thermal rearrangement (400°C, 0.2 mmHg) to the quinolizidin-2-one (62). 

Indole alkaloids Spiro isomers of the oxindole alkaloids from the genus Mytragyna Partition Clg/Corasil Methanol/water (80 20)... 

Studies detailing the thermal and photochemical reactions of these compounds are rare. The l-oxa-2,4-diazine 63 is known, from H NMR, to be in equilibrium with the spiro isomer 64, with the former predominating. Heating this mixture above 40 °C results in decomposition to acetonitrile, methyl isocyanate, and benzene (Scheme 4) <1995H(40)619>. The formation of compounds such as 63 (and 64) by cycloaddition of nitrile oxides to 8-azahepta-fulvenes is discussed in Section 9.05.10. 

Mikami developed a highly enantioselective spiro cyclization of 1,6-enynes 37 with cyclic olefin catalyzed by cationic skewphos rhodium(I) complex. This is the first example of Rh(I)-mediated spiro-construction via an ene-type cyclization (Scheme 9.10) [19]. The ene cyclization provided two spiro isomers 38 and 39, and the selectivity was found to be dependent on the substitution and on the temperature of the reaction. Interestingly, the use of the less rigid chiral diphos-phane (5,S-skewphos) gave better results in term of enantioselectivity compared to atropisomeric diphosphanes, thereby demonstrating the interest of conformational flexibility of the active rhodium species. 

The reaction of arylnitrile oxides with 1,1-diphenylallenes gave a mixture of 4-methylene-2-isoxazolines (Scheme 106) with major attack at the C(2)—C(3) double bond (74JCS(P2)l30l, 76CSC67, 76CSC71, 72JCS(P2)1914) and not a mixture of the 4- and 5-methylene compounds. 1-Phenoxyallene and benzonitrile oxide produced a mixture of positional isomers and a spiro compound (Scheme 107) (79JOC2796). 

An ipso attack on the fluorine carbon position of 4-fIuorophenol at -40 °C affords 4-fluoro-4-nitrocyclohexa-2 5-dienone in addtion to 2-nitrophenol The cyclodienone slowly isomenzes to the 2-nitrophenol Although ipso nitration on 4-fluorophenyl acetate furnishes the same cyclodienone the major by-product is 4 fluoro-2,6-dinitrophenol [25] Under similar conditions, 4-fluoroanisole pnmar ily yields the 2-nitro isomer and 6% of the cyclodienone The isolated 2 nitro isomer IS postulated to form by attack of the nitromum ion ipso to the fluorine with concomitant capture of the incipient carbocation by acetic acid Loss of the elements of methyl acetate follows The nitrodienone, being the keto tautomer of the nitrophenol, aromatizes to the isolated product [26] (equation 20) Intramolecular capture of the intermediate carbocation occurs in nitration of 2-(4-fluorophenoxy)-2-methyIpropanoic acid at low temperature to give the spiro products 3 3-di-methyl-8 fluoro 8 nitro-1,4 dioxaspiro[4 5]deca 6,9 dien 2 one and the 10-nitro isomer [2d] (equation 21)... 

Formation of the six-membered ring on cyclization of the ( )- and (Z)-4-nonenylhydroxylac-tams [E)-4 and (Z)-4 in formic acid, occurs completely stereoselectivcly to afford the 6.6-spiro compounds (7R )-5 and (7S )-5, respectively51,52. The reaction supposedly proceeds via a chair-like transition state, as depicted. Depending on the reaction conditions, however, 0.5 % 2 or about 25%51 of the five-membered ring isomers are also formed. 

Benzo[fl]- (a), benzo[fc]- (b) and benzo[c]flnorenes (c) bearing a diene group (93) in spiro geometry are three possible combinatorial isomers wherein the direction of fnsion of the naphthalene is different (Fig. 15). The n reaction centers of the diene gronps are snbject to spiro-conjngation [98, 99, 102] with the planar aromatic n system. The effect of perturbation arising from spiro-conjngation on... 

The spiro dimer of a-tocopherol (9, see also Fig. 6.4) is formed as mixture of two diastereomers by dimerization of the o-QM 3 in a hetero-Diels-Alder reaction with inverse electron demand. Both isomers are linked by a fluxion process (Fig. 6.22), which was proven by NMR spectroscopy.53 The detailed mechanism of the interconversion, which is catalyzed by acids, was proposed to be either stepwise or concerted.53-55... 

The reaction of spiro hydrophosphorane 70 (R = H) with 3 equiv of alkyllithium reagents, followed by addition of HC1, gave monocyclic hydrophosphorane 133 with the hydride in the apical position (Equation 10). Isomers with intramolecular hydrogen bonding and intermolecular bonding to a solvent molecule were separated and characterized by X-ray crystallography <1996TL8409>. 

Reactions of arylsulfonylallenes with 3,5-dichloro-2,4,6-trimethylbenzonitrile oxide (227) proceed in a manner similar to that of the above-mentioned sulfides. Probably, both 4- and 5-alkylidene-4,5-dihydroisoxazole cycloadducts are initially formed which then undergo different transformations. 4-Alkylidene isomers give spiro adducts such as 60 with an additional molecule of nitrile oxide, while 5-isomers convert to isoxazoles 61, products of their prototropic rearrangement. 

A different approach involving cyanohydrin formation from the 3-keto sugar was also explored in the D-Fru series (Scheme 17). A mixture of epimeric cyanohydrins was quantitatively formed by reaction with sodium cyanide in methanol, albeit without stereoselectivity. Chromatographic separation of (R)- and (A)-isomers was straightforward and the former epimer was selected to exemplify the two-step transformation into an OZT. Reduction of this nitrile by lithium aluminum hydride led to the corresponding aminoalcohol, which was further condensed with thiophosgene to afford the (3i )-spiro-OZT in ca. 30% overall yield. Despite its shorter pathway, the cyanohydrin route to the OZT was not exploited further, mainly because of the disappointing yields in the last two steps. 

Aramaki and Atkinson were also active in work on the spiro-oxazines [65]. They noted that for NOSH in many polar and nonpolar solvents the picosecond time-resolved resonance Raman spectra simply built up over 50 psec with no shape evolution. The same finding was concluded from transient absorption measurements over the same time scale. The spectra/absorbances were then constant for 1.5 nsec. These authors suggest that only two isomers can be expected to contribute to the merocyanine spectra because those trans about the y-methene bridge bond attached to the naphthalene ring are sterically crowded due to short interproton distances. There was no evidence for the X transient in their study however, the 50-psec convoluted pulse profile may be expected to mask this sortlifetime species even if it were present. 

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