The Grob Fragmentation

1. Special Topic The Grob Fragmentation Rachel Atkinson 09.05.12

2. Cyril A. Grob (1917 – 2003) - Born in London to Swiss parents in 1917- Studied Chemistry at ETH Zurich- Carried out a PhD for Leopold Ruzicka (Nobel Prize in Chemistry 1939)in 1943 on artificial steroidal antigens- Moved to Basel and worked with Taddeus Reichstein at aPharmaceutical Institute then for the Organic Chemistry section of the University in 1947- Became director of the Institute then in 1960 became the chair-In 1987 he was given emeritus status- 15th December 2003 he died at home in Basel aged 86 Angew. Chem. Int. Ed. 2004, 43, 4392

3. Cyril A. Grob research Biotin Lysergic acid His initial research was on natural products, He carried out synthetic studies on:- Biotin- Lysergic acid-The steroid framework He also performed a synthesis of Sphingosin Following a research stay at University of California in 1951/1952 his research changed to: The elucidation of reaction mechanisms Looking at structure-reactivity relationships Angew. Chem. Int. Ed. 2004, 43, 4392

4. Discovery of the Grob fragmentation An investigation of the reductive elimination of bromine from 1,4-dibromides in the presence of zinc led in1955 to the recognition of heterolytic fragmentation as a general reaction principle. The elimination of the halogen from saturated 1,4-dihalides led to the formation of two olefinic bonds. The structural and stereochemical prerequisites for a fragmentation to occur were investigated with model systems, such as γ-aminohalide or γ-aminosulfonates: The heterolyticfragmentation is now termed the Grob fragmentation These studies also led to the elucidation of the mechanism of the Beckmann rearrangement. Angew. Chem. Int. Ed. 2004, 43, 4392; Helv. Chim. Acta1955, 38, 94; Angew. Chem. 1969, 81, 543

5. The general mechanism Grobfragmentation: An interesting and generally useful skeletal transformation, involving specific carbon-carbon bond cleavage with accompanying conversion of certain sigma-bonds to pi-bonds. An electrofuge is a leaving group, which does not retain the bonding pair of electrons from its previous bond with another species. A nucleofuge is a leaving group, which retains the lone pair from its previous bond with another species 1)http://www2.chemistry.msu.edu/faculty/reusch/virttxtjml/rearang2.htm 2)Grob fragmentation, MariuszBobin, University of Sussex http://web.me.com/e.m.e.viseux/EDDY_M_E_VISEUX_-_CHEMISTRY_-_University_of_Sussex/Name_Reactions/Entries/2011/2/17_Grob_Fragmentation_files/Grob%20Fragmentation.pdf

6. Other reaction paths for this system In nucleophilic solvent; water or alcohol it is possible for alternative reactions to occur: Substitution of the nucleofugal group X with the solvent Elimination of the nucleofugal group X Attack of the lone pair on the electrofugal group(a) on d and loss of the nucleofugal group X resulting in ring closure Fragmentation is the main pathway, as the alternative routes can be disfavoured or excluded by optimisation of the stereoelectronicgeometries or due to ring strain in cyclic substrates. 1) Angew. Chem. 1969, 81, 543 2)Grobfragmentation, MariuszBobin, University of Sussex

7. Three potential mechanisms for the Grob There are three potential mechanisms as the bond break sequence may occur as a one or two stepped process: Certain structural and stereoelectronic requirements determine which mechanism is used. These are similar mechanisms to the known 1,2 elimination to give olefins. 1) Angew. Chem. 1969, 81, 543 2)Grobfragmentation, MariuszBobin, University of Sussex

8. Three potential mechanisms for the Grob One stepped process, simultaneous loss of the electrofugal group and nucleofugal group 1) Angew. Chem. 1969, 81, 543 2)Grobfragmentation, MariuszBobin, University of Sussex

9. Three potential mechanisms for the Grob 2) Two stepped process, firstly loss of X generating a carbocation then break down to the two olefinic species if following the fragmentation route (similar to E1 or SN1) However the carbonium ion can further react via elimination, substitution, or ring-closure. The rate-determining step is the ionization to the carboniumion. The tendency to ionize is greater when a tertiary and thus stable carbonium ion is formed. The leaving ability of X- is important as it can lead to an increased ionization rate (e.g. Cl< Br < I) 1) Angew. Chem. 1969, 81, 543 2)Grobfragmentation, MariuszBobin, University of Sussex

10. Three potential mechanisms for the Grob 3) Two stepped process, firstly loss of electrofugal group generating a carbanionic species then break down to give olefin and release of X (rarer) This can only occur if the carbanionis stabilized by electron-withdrawing substituents and if X is a poorer leaving group. 1) Angew. Chem. 1969, 81, 543 2)Grobfragmentation, MariuszBobin, University of Sussex

11. The synchronous mechanism Involves 5 atomic centres of 1 molecule in a transition state therefore requiring rigorous structural and stereoelectronic requirements. The orbitals of the bonding and non-bonding electron pairs participating in the reaction must be aligned properly, i.e. the non-bonding pair of the nitrogen (e.g. a) and the bonding pairs in the green-coloured covalent bonds(the reacting electron pairs, b-c and d-x) are anti relative to the brown bonds (a-b and c-d). This is the preferred configuration for maximum overlap. 1) Angew. Chem. 1969, 81, 543 2)Grobfragmentation, MariuszBobin, University of Sussex 3)http://www2.chemistry.msu.edu/faculty/reusch/virttxtjml/rearang2.htm

12. The anti-peri planar configuration The lone pair on O, the C2-C3 and C1-Y σ-bonds must be anti-periplanar for maximal orbital overlap in the transition state of the p-orbitals in the newly formed π-bond. The relative configuration at C1 and C2 is transformed into the E/Z geometry of the olefin. The all-anti-periplanar arrangement is met in the staggered conformation IVaand its rotamersIVb and IVcaround C2-C3, but rotation around C1-C2 leads to unfavorable conformations. Chem. Rev. 2010, 110, 3741 - 3766

13. An example of anti-peri planar In the cyclic templates 35-39, the C1-C2-C3-conformationsare fixed. The anti-peri planar arrangement is present in 36-39, but not in 35. 36-39undergo Grob fragmentation, and 35 does not. Chem. Rev. 2010, 110, 3741 - 3766

14. Exceptions As with any rules there are always exceptions and for some molecules the syn geometry is preferred. An example of this is the Grob fragmentation occurs for the endo epoxide (52) but not the exo. It is thought the endois better suited to the fragmentation due to the high co-planarity of the orbitals. Chem. Rev. 2010, 110, 3741 - 3766

15. Examples of the Grob fragmentation In 1955 this was one of the first fragmentation reactions discovered by Grob: However in 1952 Eschenmoser had discovered a base catalysed reaction, despite the previous work, this elimination reaction taking place when an electrofuge and nucleofuge are situated in positions 1 and 3 on an aliphatic chain was termed the Grob fragmentation. Another example of a Grob fragmentation is the retro-aldol reaction: 1) Chem. Rev. 2010, 110, 3741 – 3766 2)http://www2.chemistry.msu.edu/faculty/reusch/virttxtjml/rearang2.htm

16. Carbonyl generating Grob fragmentation Chem. Rev. 2010, 110, 3741 - 3766

17. Carbonyl generating Grob fragmentation Carbonyl generation via ring cleavage reactions: Monosulphanated 1,3,diols: Basic deprotonation then fragmentation from anion formed Forming a lavandulyl system Stereospecificsynthesis of acyclic trisubstituted olefin subunits in cecropiajuvenile hormone: This fragment was built based on a repetition sequence Chem. Rev. 2010, 110, 3741 - 3766

18. In total synthesis This clearly indicates the anti-peri planar arrangement necessary for the Grob fragmentation In total synthesis: The total synthesis of pallavicininand neopallavicininrelied on a Grob fragmentation to generate the vinyl moiety in, which is present in both targets: Chem. Rev. 2010, 110, 3741 - 3766

19. Β-hydroxy ketones Fragmentation from β-hydroxy ketones: Addition of OH nucleophile to carbonyl followed by fragmentation: Applied to the formation of cis-Chrysanthemic Acid In a model system for the synthesis of moenocinol, Grob fragmentation was used to introduce the exomethylenemoiety Chem. Rev. 2010, 110, 3741 - 3766

20. Alternative conditions Fragmentation can also be induced under different condition to base. LHS shows a reductive mechanism followed by a Grob fragmentation RHS shows a Grignard mediated reaction then it undergoes a Grob fragmentation Chem. Rev. 2010, 110, 3741 - 3766

21. Other leaving groups An example that has the halide leaving group rather than the tosyl or mesyl groups Formation of an Insect pheromone Ammonium leaving group: Quaternary γ amino alcohols give access to unsaturated aldehydes and ketones with a Z double bond Chem. Rev. 2010, 110, 3741 - 3766

22. Acid catalysed fragmentation Lewis acid-mediated fragmentation gave the desired (Z)-Olefin exclusively. This result indicates that the configuration of the epoxide has no effect on the Grob fragmentation. Allylicalcoholwas further converted to the ester side chain of disdemnaketalA, a HIV protease inhibitor. Acid catalysed acetal opening by an antiperi planar arrangement Chem. Rev. 2010, 110, 3741 - 3766

23. Carbonyl generating Grob fragmentation Bicyclo[5.4.0]undeconone was synthesised via a ring expanding Grob fragmentation Carbonyl generation via ring expansion reactions: In the synthesis of parvifoline, a 5,5-ring system was used to generate the eight-membered ring When 240 was treated with sodium methoxide under reflux, a Grobfragmentation occurred to form cyclooctenone Chem. Rev. 2010, 110, 3741 - 3766

24. Total synthesis In 2000, in the total synthesis of coraxeniolide A was generated by Grobfragmentation. Treatment with sodium hydride led to the unsaturated nine-membered ring . In 2008, Corey published an enantioselective synthesis of caryophyllene. The nine membered ring was generated by fragmentation of diolto dienone. Dienone258 was also an intermediate in his synthesis of coraxeniolide A. Chem. Rev. 2010, 110, 3741 - 3766

25. Difficult to generate double bond A fragmentation was used to overcome the inherent ring strain of the decahydro-1,5-butanonaphthalene system in intermediate 273. The tetracyclic precursor 272 was prepared by two Diels-Alder reactions. Grob fragmentation of monomesylateddiol272 with KHMDS was used to form the tricyclic core Barans approach to Vinigrol: Chem. Rev. 2010, 110, 3741 - 3766

26. Enolate induced Grob fragmentation An enolate is generated by deprotonation with KHMDS and then a Grob fragmentation occurs leading also to ring opening: Chem. Rev. 2010, 110, 3741 - 3766

27. Different electrofugal groups Boronic esters can also be used as electrofugal groups as shown in the e.g. below: Eschenmoserssynthesis of macrolides: Decarboxylative fragmentation can occur a double Grob type fragmentation occurs of an amidinium salt forming an unsaturated lactone Chem. Rev. 2010, 110, 3741 - 3766

28. Tandem reactions Tandem aldol-Grob fragmentation Thefirst step was the LA-mediated aldol addition between aldehyde and ketone. Next, the newly formed hydroxyl group attacked the activated carbonyl whose fragmentation led to olefin. s leading also to ring opening: Tandem Semipinacol rearrangement-Grob fragmentation: (a NBS promoted semipinacolrearrangement) Acyclic substrates = a one-step anti-periplanar fragmentation Cyclic substrates = a two-step syn-fragmentation Chem. Rev. 2010, 110, 3741 - 3766

29. Conclusion -Grob fragmentation:Fragmentation substrates are typically 1,3-diheterofunctionalized compounds featuring a nucelophilic atom with a negative charge or lone electron pair (electrofuge) and a leaving group (nucleofuge) in a 1,3-relationship. - Double bonds are generated in the fragmentation - It has been shown to work for usually hard to generate double bonds (Baron example) - Generally if all the stereochemical requirements are met for a concerted mechanism (i.e. an anti-peri planar relationship) side reactions can be suppressed and you get a fast, high yielding reaction under simple base or acid catalysed conditions - It has also been used in more complex systems in one pot methods and tandem reactions Chem. Rev. 2010, 110, 3741- 3766; Angew. Chem. Int. Ed. 2004, 43, 4392 Heterolyric fragmentation article: Angew.Chem. Int. Ed, 1967, Vol 6, No 1, 1-15 (Grob and Schiess)