Spiro-diastereomers

The oxidation of a-tocopherol (1) to dimers29,50 and trimers15,51 has been reported already in the early days of vitamin E chemistry, including standard procedures for near-quantitative preparation of these compounds. The formation generally proceeds via orf/zo-quinone methide 3 as the key intermediate. The dimerization of 3 into spiro dimer 9 is one of the most frequently occurring reactions in tocopherol chemistry, being almost ubiquitous as side reaction as soon as the o-QM 3 occurs as reaction intermediate. Early accounts proposed numerous incorrect structures,52 which found entry into review articles and thus survived in the literature until today.22 Also several different proposals as to the formation mechanisms of these compounds existed. Only recently, a consistent model of their formation pathways and interconversions as well as a complete NMR assignment of the different diastereomers was achieved.28... 

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 methano-dimer of a-tocopherol (28)50 was formed by the reaction of o-QM 3 as an alkylating agent toward excess y-tocopherol. It is also the reduction product of the furano-spiro dimer 29, which by analogy to spiro dimer 9 occurred as two interconvertible diastereomers,28 see Fig. 6.23. However, the interconversion rate was found to be slower than in the case of spiro dimer 9. While the reduction of furano-spiro dimer 29 to methano-dimer 28 proceeded largely quantitatively and independently of the reductant, the products of the reverse reaction, oxidation of 28 to 29, depended on oxidant and reaction conditions, so that those two compounds do not constitute a reversible redox pair in contrast to 9 and 12. 

FIGURE 6.23 Methano-dimer of a-tocopherol (28) formation and redox reactions, including oxidation to the two fluxationally interconvertible diastereomers of furano-spiro dimer 29. 

A further hetero-Diels-Alder reaction with inverse electron demand between o-QM 3 as the dienophile and either of the two diastereomers of spiro dimer 9 as the diene provided the spiro trimers 31 and 32 (Fig. 6.25). The absolute configuration was derived from NMR experiments. It was moreover shown that only two of the four possible stereoisomeric trimers were formed in the hetero-Diels-Alder reaction the attack of the o-QM 3 occurred only from the side syn to the spiro ring oxygen.28... 

FIGURE 6.25 Spiro trimers of a-tocopherol (31, 32) formed by reaction of o-QM 3 with the two diastereomers of spiro dimer 9. 

Irradiation of the sodium salt 517 in a solution of maleonitrile in THF gave a 30% yield of the as-spiro[2.6]nonatrienedicarbonitrile 524 (Scheme 6.106). Analogously, fumaronitrile led to the trans-diastereomer 525 exclusively in 29% yield [193b], which was also obtained from (trimethylsilyl)tropylium tetrafluoroborate (519) as precursor of 5 [208]. The interception of 5 by dimethyl fumarate succeeded by generating 5 from 517 by either photolysis [193] or thermolysis [193, 194] and from 519 [208] and afforded the dimethyl trans-dicarboxylate 526 in yields of 50, 40 and 42%, respectively. Liberation of 5 in the presence of dimethyl maleate led also to 526 [194, 214], In this reaction, the isomerization of dimethyl maleate to fumarate could have interfered and hence pretended the loss of the stereochemical information, since... 

Nair and co-workers reported the diastereoselective synthesis of spiro y-butyro-lactones from 1,2-dicarbonyls [125]. The authors studied the reaction with 1,2-cyclohexane dione 230 which produces the desired lactone 232 in good yields Eq. 22a. Isatins 233 are more reactive, but the products 235 are obtained as a 1 1 separable mixture of diastereomers Eq. 22b. The Nair research group extended this methodology to include homoenolate addition to tropanone 236 to form bicyclic 5-lactones 238 Eq. 22c [126]. 

Padwa has shown that rhodium-catalyzed oxidation of indolyl carbamate 67 employing either Phl(OAc)2 or Phl=0 follows a path similar to that of the D-aUal carbamate (Scheme 17.26) [95]. In principle, indole attack of the putative rhodium-nitrene generates zwitterion 68, which is trapped subsequently by an exogenous nucleophile. Spiro-oxazolidinone products (for example, 69) are isolated as single diastereomers in yields ranging from 50 to 85%. As an intriguing aside, Padwa has found that certain carbamates react with Phl=0 in the absence of any metal catalyst to furnish oxazoHdinone products. This result may have implications for the mechanism of the rhodium-catalyzed process, although it should be noted that control experiments by Espino and Du Bois confirm the essential role of the metal catalyst for C-H amination [57]. 

Treatment of 5-methylene-3,3-dimethyl-3,4-dihydrotriazole (77) with acrylonitrile gave aza-spiro[3.2]hexane (78) as a 1 1 mixture of diastereomers (Equation (25)) <86CC172l>. 

Calculations by PM3 methods have been carried out on molecules such as the diastereomers of methyl 4-(dimethyl-amino)-5-methyl-2-phenyl-5,6-dihydro-4//-l,3-thiazine-5-carboxylate, and the /ra j-diastereomer 3 was shown to be significantly more stable than the corresponding m-diastereomer 4 <2002TL6067>. The structure of the spiro compound 5, which acts as a charge-transfer dye, was calculated by PM3 methods <1996JA1471>. 

The cyclic ammonium ylide/[l,2]-shift approach has been successfully applied by West and Naidu to a key step in the total synthesis of (—)-epilupinine, one of the biologically active lupin alkaloids. Cu(acac)2-catalyzed diazo decomposition of enantiomeric pure diazoketone 160 in refluxing toluene generates a spiro ammonium ylide 161 and 162, which then undergoes [l,2]-shift to give rise to a quinolizidine skeleton as a mixture of diastereomers (95 5) (Scheme Major diastereomer 164 has enantiomeric purity of 75% ee. The partial retention of stereo-... 

More recently, Naidu and West have utilized a ring expansion reaction of spiro azetidinium ylide 167 in the synthesis of pyrrolizidine alkaloids. Spiro azetidinium ylide 167 is generated through a Cu(acac)2-catalyzed intramolecular reaction of a copper carbene complex with a pendant amino moiety. Subsequent [l,2]-shift gives fused bicyclic products 168 and 169 as a diastereomeric mixture. Each diastereomer was further converted to naturally occurring pyrrolizidines ( )-turneforcidine and ( )-platynecine, respectively (Scheme 18). ... 

This strategy has been extended to generate spiro derivatives from appropriate hydroxyalkylidene precursors (83BCJ2652). The salicylidene derivative (164) has also been similarly cyclized (84CL130I) by treatment with t-butyl hypochlorite to yield a mixture of diastereomers (Scheme 54). 

The preparation of the allene bis-epoxide 1 started with isovaleraldehyde 9. Addition of the protected propargyl alcohol 10 under the Carreira conditions led to 11 in > 95% . Mesylation followed by displacement with methyl cuprate provided the allene without loss of enantiomeric excess. Oxidation of the allene 12 with dimethyldioxirane could have led to any of the four diastereomers of the spiro bis epoxide. In the event, only two diastereomers were observed, as a 3 1 mixture. That 1 was the major diastereomer followed from its conversion to 3. The configuration of the minor diastereromer was not noted. Exposure of 1 to nucleophilic azide then gave the easily-purified 2. 

The lactone 88 having an exo-cyclic double bond was applied in a 1,3-dipolar cycloaddition with nitrile oxides in recent work by Gallos et al. (Scheme 12.29) (133). The spiro-isoxazoline (89) was obtained as the sole diastereomer from the addition of the stable nitrile oxide 87. The resulting adduct 89 was further subjected to N—O bond cleavage by hydrogenolysis, followed by a spontaneous cyclization to give the carbocyclic product 90 in 64% yield. 

In two steps, Wang and Ganesan convert 4 first into the a,/l-unsaturated imine 6 and then, by an acyliminium Pictet-Spengler condensation, into the /i-carboline 8 (Scheme 1) [5]. The trans diastereomer was formed as a side product, and had to be separated. Treatment of 8 with NBS in aqueous acetic acid by a procedure described in 1969 by van Tamelen [6] results in the formation of the oxindoline 9 through a spiro ring-contraction. The intermediate bromonium ion is generated on the less hindered a-face, in the position opposite to the... 

In the alternative Mannich route to the spiro intermediate 14, the indole ring of 4 is oxidized first. The resulting oxoindoline 11 is then converted by treatment with senecialdehyde (5, prenal ) into a mixture of four diastereomers of compound 12, which are acetylated, as a mixture, to 14. The two total syntheses differ with respect to the formation of the diketopiperazine structure and the introduction of the C8-C9 double bond of spirotryprostatin B (2), with quite divergent overall yields. 

The synthesis of complex polycyclic molecules has been achieved by Montgomery et al. by cascade cyclization processes involving nickel enolates [40]. Up to three cycles could be generated in the intramolecular version of the reaction. Alkynyl enal or enone were first converted into their corresponding seven-membered cyclic enolates in the presence of Ni(cod)2/TMEDA [41 ]. These species could be trapped by electrophiles such as aldehydes. For example, upon treatment with the nickel catalyst, dialdehyde 32 afforded spiro-cycle 35 in 49% yield as a single diastereomer (Scheme 17). 

Spiropyrans SP-2, reported by Miyashita et al., forming chromium complexes on their indoline phenyl ring, can possibly take two diastereomeric spiro forms >[47]. Because of the favorable interaction of the pyran oxygen atom and the chromium atom, the thermal ring closure occurred diastereomerically to give only one diastereomer from the planar merocyanine form generated by photoirradia-... 

The reaction of 13, in which the (3-pyridyl)carbonyloxy groups can be either in syn or in anti position, with spiro[cyclopropene-3,9 -fluorene] creates two new stereogenic centers.35 Thus two diastereomers are possible for each the syn- and the anri-isomer which form a pair of C2-symmetrical enantiomers (R,R/S,S) and a Cs- or Cj-symmetrical meso form (R,S) n The resulting calixarenes 14, bearing dihydroindolizine units, were studied as chromogenic compounds ( calixo-chromes ) in quenching experiments not related to their chirality. 

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