Bicyclic substrate

The high chemoselectivity for the Baeyer-Villiger process was utilized in the synthetic elaboration of another hetero-bicyclic substrate. The biooxidation only provides the expected unsaturated lactone in a desymmetrization reaction without compromising the olefin functionality. The biotransformation product was then converted to pivotal intermediates for C-nucleosides like showdomycin, tetrahydro-furan natural products like kumausyne, and goniofufurone analogs in subsequent chemical operations (Scheme 9.17) [161]. 

It was shown74 that the folded conformation of bicyclic substrates is a prerequisite for isomerizations such as 177 - 178. Thus, vyw-9-vinyl triene 183, being in the open conformation, undergoes an unusual Cope rearrangement to give the intermediate 184 which starts a cascade of thermal isomerizations at 60-65 °C (equation 57) whereas the awft -9-vinyl epimer 185 rearranges into the indene derivative 186 at 110°C in benzene solution (equation 58)74. 

Lithium metal or alkyllithium derivatives react with dihalocyclopropanes to provide the corresponding lithiohalocyclopropanes I which are stable at temperatures around —100 °C. These metalated species are easily trapped with electrophiles (R—X) like methyl or ethyl iodide, trimethylstannyl chloride, tri-methylsilyl chloride etc. In the case of the unsaturated bicyclic substrate II a double bond migration is observed, which in the presence of excess starting bromide is accompanied by isomerization of the axo-lithio intermediate III to its endo-isomer IV [58],... 

The reaction is of importance for bicyclic substrates. Thus, homochiral verbenone derivatives 1 could be transformed to new building blocks 2 for chiral pool syntheses.142-144... 

Most such heterobicyclic substrates are fused pyrazines from which the second ring must be removed completely or in part by oxidation, hydrolysis, or some other means to afford the desired monocyclic pyrazine derivatives. However, some such bicyclic substrates do not already incorporate a pyrazine ring, so that more profound processes (like rearrangement, ring expansion, or use of a cosynthon) must be employed to furnish pyrazines. 

The various syntheses are classified simply according to the bicyclic substrate systems in alphabetical order. 

Nitrosyl halides add to alkenes references are scattered through the litnnture back to 1875 (ref. 194 and references cited therein). The adducts vary enormously in their stability, but when their structures allow they, like nonhalogenated nitroso compounds, isomerize to oximes or dimnize. The orientation of the reaction is consistent with an electrophilic medumism, in which the reagent is polarized as NO Hat. Bicyclic substrates and reaction media of low polarity favor syn addition, suggesting a four-center transition state (Scheme 81). Aziridine synthesis via NOCl/alkene adducts is discussed in Section 3.5.2.1. 

As with some of the racemic ketones discussed previously (Schemes 27,29, 30, 31 and 37), reductions of bicyclic substrates to all possible stereoisomeric products can be achieved. The BY-mediated reduction of ( )-(86) to (92) and (93)>35 establishes this point (Scheme 39) and contrasts the more specific TBADH-promoted reaction of Scheme 38. >3 ... 

This approach was not limited to the bicyclic substrates and was applied also to steroid derivatives (e.g. 8). ... 

Similar trends in stereoselectivity are observed with homoallylic bicyclic substrates [119]. When racemic substituted pyrans are treated in THF, with the previous catalyst at 70 °C in 30 min, a kinetic resolution leads to the unreacted pyran in >99% ee in approximately 35-40% yield [123] (Scheme 7-105). 

Using these criteria 45 substrates for which experimental information was available for reaction at pH 7 were chosen to construct the model (Table 3). There is a significant amount of literature data for substrates of HLADH which lack information on enantiomeric excess values and absolute configurations of products and where the relative rates of reaction have been measured under different reaction conditions (e.g. pH 8.5). Substrates falling into this category (46-69, Table 4) were not used. Heterocyclic bicyclic substrates 70-73 were only used for testing. 

Bicyclic systems have provided an interesting framework for examination of stereochemical preferences in the rearrangements of diol monoethers. Monti et al. found that the anti (double bond and hydroxy group) isomer of the [2.2.2] bicyclic substrate (49) gave (50) stereospecifically, whereas the syn isomer gave a mixture of products (equation 27). 

Further treatment of a methanolic solution of the crude -chloro ketones with sodium acetate gives a,/3-unsaturated ketones by dehydrochlorination. In the case of bicyclic substrates, the overall process corresponds to a ring enlargement. Application of this method to 1,2-bis(siloxy)cyclopropanes provides 1,3-diketones (Table 3, entry 9). ... 

The formation of an exo/en /o-isomeric mixture in the reaction with norbornene is especially remarkable as most of the [3-1-2] cycloadditions involving bicyclic substrates produce exo-configured products exclusively. The structures of cotrimers additionally formed in the reaction with norbornene (7% yield) are uncertain. 

The implications of the synchronous mechanism on the kinetics and product stereochemistry of cyclopropyl to allyl rearrangements of bicyclic substrates have already been discussed in Houben-Weyl, Vol.4/3, pp 621-630. 

It was shown " that the folded conformation of bicyclic substrates is a prerequisite for isomerizations such as 177 178. Thus, 5y -9-vinyl triene 183, being in the open... 

Figure 16.5-32. Baeyer-Villiger oxidation of various [2.2.1] bicyclic substrates.

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