Bicyclo alkyl synthesis

Scheme 13.17 depicts a synthesis based on enantioselective reduction of bicyclo[2.2.2]octane-2,6-dione by Baker s yeast.21 This is an example of desym-metrization (see Part A, Topic 2.2). The unreduced carbonyl group was converted to an alkene by the Shapiro reaction. The alcohol was then reoxidized to a ketone. The enantiomerically pure intermediate was converted to the lactone by Baeyer-Villiger oxidation and an allylic rearrangement. The methyl group was introduced stereoselec-tively from the exo face of the bicyclic lactone by an enolate alkylation in Step C-l. 

A fourfold anionic domino process consistingofadominoMichael/aldol/Michael/ aldol process was used by Koo and coworkers for the synthesis of bicyclo[3.3.1]non-anes. They employed 2 equiv. of inexpensive ethyl acetoacetate and 1 equiv. of a simple a, 3-unsaturated aldehyde [290]. Differently substituted dihydroquinolines were assembled in a Michael/aldol/elimination/Friedel-Crafts-type alkylation protocol by the Wessel group [291]. An impressive approach in this field, namely the construction of the indole moiety 2-557, which represents the middle core of the man-zamines, has been published by Marko and coworkers [292]. Manzamine A (2-555) and B (2-556) are members of this unique family of indole alkaloids which were isolated from sponges of the genus Haliclona and Pelina (Scheme 2.126) [293]. 

The full paper on the synthesis of onikulactone and mitsugashiwalactone (Vol. 7, p. 24) has been published.Whitesell reports two further useful sequences (cf. Vol. 7, p. 26) from accessible bicyclo[3,3,0]octanes which may lead to iridoids (123 X=H2, Y = H) may be converted into (124) via (123 X = H2, Y = C02Me), the product of ester enolate Claisen rearrangement of the derived allylic alcohol and oxidative decarboxylation/ whereas (123 X = 0, Y = H) readily leads to (125), a known derivative of antirride (126) via an alkylation-dehydration-epoxi-dation-rearrangement sequence. Aucubigenin (121 X = OH, R = H), which is stable at —20°C and readily obtained by enzymic hydrolysis of aucubin (121 X = OH, R = j8-Glu), is converted by mild acid into (127) ° with no dialdehyde detected sodium borohydride reduction of aucubigenin yields the non-naturally occurring isoeucommiol (128 X=H,OH) probably via the aldehyde (128 X = O). ... 

Reductive 1,3-elimination reaction of alkyl dihalides constitutes one of the classical methods for the preparation of cyclopropyl derivatives and is particularly useful for the synthesis of highly strained polycyclic hydrocarbons. A new preparation method of [l.l.ljpropellane, more versatile than the original Wiberg s method, has been devised3,4. Thus, treatment of l,l-dibromo-2,2-bis(chloromethyl)cyclopropane with alkyllithium or lithium powder affords [1.1. ljpropellane by two successive 1,3-eliminations of halogens by way of 1 -bromo-2-(chloromethyl)bicyclo[l. 1. Ojbutane (equation 1). This method has been... 

Properly alkylated bicyclo[4.2.0]-octan-2-ones formed by 2+2 photocycloaddition of alkenes to cyclohexenones cleave to 5, -unsaturated ketones, one example leading to a sesquiterpene synthesis [73]. 

The alkylation of acyclic imines with electrophilic alkenes such as acrylonitrile, methyl acrylate or phenyl vinyl sulphone is also sensitive to steric effects and again, as a consequence, only mono-alkylation occurs398. The regioselectivity of the reaction in methanol varied from 100% attack at the more substituted a-position to 70% attack at the less substituted a -position depending upon the steric inhibition manifested and the stabilization of the competing secondary enamine tautomers (vide infra) (Scheme 204). In contrast, the reaction of butanone and other methyl ketone imines with phenyl vinyl ketone occurs twice at the more substituted a-position but this is then followed by a double cyclization process (Scheme 205). Four carbon-carbon bonds are formed sequentially in this one-pot synthesis of the bicyclo[2.2.2]octanone 205 from acyclic precursors399,400. 

Intramolecular alkylation reactions employing allylsilanes have been developed. A taxoid bicyclo[9.3. l]pentadecane ring system was prepared via intramolecular alkylation of (150). It is interesting to note that the alkylation occurred in the y-position relative to the alkyne (Scheme 218). A Nicholas reaction was used in the synthesis of (+)-epoxydictymene (Scheme 219). 

The method of Huckin and Weiler has enjoyed widespread use in synthesis. For example, recently reported syntheses of rrans-bicyclo[4.3.1]decan-10-one and a bicyclo[4.4.1]undecan-7-one derivative have employed y-alkylations of 3-keto ester dianions as key steps. This methodology has also been extended to the formation and y-alkylation of dianions of y,8-unsaturated P-keto esters. ... 

The alkylation of 2-alkyl-substituted sulfolenes takes place with complete regio- and high stereo-selectivity to yield approximately 60% of rra/ -2,5-disubstituted 3-sulfolenes. When 1,4-diiodobutane and 1,3-diiodopropane are used instead, one-pot dialkylation occurs at the 2-position in the first case and leads to a spiro sulfolene, whereas 2,3-dialkylation proceeds in the second case leading to a fused bicy-clic product. Interestingly 2,S-dialkylation has been achieved, from 3-bromo(bromomethylpropene), thus allowing the synthesis of bicyclo[3.2.1]sulfones. ... 

Brefeldin (20) is a 13-membered lactone isolated from a number of sources and has a wide spectrum of biological activity. Many of the syntheses of this lactone use alkynes as intermediates. Thus, Living-house and Stevens used an elegant ring opening of a bicyclo[3.1.0]hexane to give the desired trans stereochemistry (Scheme 38), whereas in the synthesis of Kitahara and coworkers, a more conventional alkynide alkylation was involved (Scheme 39). 

The range of cyclopropenes made by this route is not large and they are mostly simple alkylated cyclopropenes, but they do include a few not readily available in other ways most notably the bicyclo[4.1.0]heptenes 1 and the equivalent bicyclo[5.1.0]octenes. ° " The synthesis of the unstable 7,7-dimethylbicyclo[4.1.0]heptene (1) serves to illustrate an unusual side reaction sometimes encountered in the photolysis of 3/7-pyrazoles, namely formation of the valence tautomer The reaction is only observed at low temperatures and, as shown, the balance... 

A process that has proved valnable in synthesis is the addition of singlet oxygen to A-alkyl- and especially A-acyl-pyrroles ° prodncing 2,3-dioxa-7-aza-bicyclo[2.2.1]heptanes, which react with nncleophiles, such as silyl enol ethers, mediated by tin(II) chloride, generating 2-substitnted-pyrroles that can be nsed, as the example shows, for the synthesis of indoles via intramolecular electrophilic attack by the carbonyl group at the pyrrole P-position. 

A synthetically useful example of this process is the conversion of 117 to 120, which involves a 1,2-alkyl shift, and was part of Hwu s synthesis of (-)-solavetivone. 38 jhe alkyl fragment is actually part of the bicyclic ling system, one arm of the bicyclo[4.4.0]decane ring system. Reaction of the OH unit with the Lewis acid resulted in formation of the tertiary cation 118, which was followed by a 1,2-alkyls shift to give 119, where the new cation is stabilized by the adjacent silicon of the trimethylsilyl group. 39 Loss of the trimethylsilyl group from 119 gives spiran (120). 

In general, photolytic azo-extrusion from 4,5-dihydro-3/f-pyrazoles is superior to thermolysis. Photolysis was introduced as a method for synthesis by Jeger s group (Kocsis et al., 1960). The configurations of the products in the thermolysis, in the direct photolysis, and in the sensitized photolysis are often quite different. Cyclopropanation for the synthesis of alkyl cyclopropanes via dihydropyrazoles is preferred to the direct route via carbenes, because, in the latter, the C - H insertion of the carbene into the alkyl group is faster than the cyclopropanation. The dihydro-pyrazole pathway was used in particular for the formation of highly strained bicyclo[1.1.0]butanes (Franck-Neumann, 1967 Komendantov and Bekmukhametov, 1971 6.89) and bicyclo[2.1.0]pentanes (Vogelbacher et al., 1984 6.90). 

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