The Grob Fragmentation Rachel Atkinson 09.05.12 Special Topic.

The Grob Fragmentation

Rachel Atkinson09.05.12

Special Topic

- 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

Cyril A. Grob (1917 – 2003)

• 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

Cyril A. Grob research

Biotin Lysergic acid

Angew. Chem. Int. Ed. 2004, 43, 4392

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 heterolytic fragmentation is now termed the Grob fragmentation

These studies also led to the elucidation of the mechanism of the Beckmann rearrangement.

Discovery of the Grob fragmentation

Angew. Chem. Int. Ed. 2004, 43, 4392; Helv. Chim. Acta 1955, 38, 94; Angew. Chem. 1969, 81, 543

C C C XN N+ X-+ +

regulated cleavageinto 3 fragments

X = halogen or OSO2R

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

The general mechanism

Grob fragmentation: An interesting and generally useful skeletal transformation, involving specific carbon-carbon bond cleavage with accompanying conversion of certain sigma-bonds to pi-bonds.

1)http://www2.chemistry.msu.edu/faculty/reusch/virttxtjml/rearang2.htm2)Grob fragmentation, Mariusz Bobin, 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

In nucleophilic solvent; water or alcohol it is possible for alternative reactions to occur:

1) Substitution of the nucleofugal group X with the solvent2) Elimination of the nucleofugal group X

3) 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 stereoelectronic geometries or due to ring strain in cyclic substrates.

Other reaction paths for this system

1) Angew. Chem. 1969, 81, 5432)Grob fragmentation, Mariusz Bobin, University of Sussex

There are three potential mechanisms as the bond break sequence may occur as a one or two stepped process:

Three potential mechanisms for the Grob


Certain structural and stereoelectronic requirements determine which mechanism is used. These are similar mechanisms to the known 1,2 elimination to give olefins.

1) One stepped process, simultaneous loss of the electrofugal group and nucleofugal group



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 carbonium ion. 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)



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 carbanion is stabilized by electron-withdrawing substituents and if X is a poorer leaving group.



- 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.

The synchronous mechanism

1) Angew. Chem. 1969, 81, 5432)Grob fragmentation, Mariusz Bobin, University of Sussex3)http://www2.chemistry.msu.edu/faculty/reusch/virttxtjml/rearang2.htm

The anti-peri planar configuration

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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 IVa and its rotamers IVb and IVc around C2-C3, but rotation around C1-C2 leads to unfavorable conformations.Chem. Rev. 2010, 110, 3741 - 3766

An example of anti-peri planar

In the cyclic templates 35-39, the C1-C2-C3-conformations are fixed.The anti-peri planar arrangement is present in 36-39, but not in 35. 36-39 undergo Grob fragmentation,and 35 does not.

Chem. Rev. 2010, 110, 3741 - 3766

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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 endo is better suited to the fragmentation due to the high co-

planarity of the orbitals.

Chem. Rev. 2010, 110, 3741 - 3766

HH

OH

H

O

HH

+OH

H

O-

O- +OH OOH

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 positions1 and 3 on an aliphatic chain was termed the Grob fragmentation.

Another example of a Grob fragmentation is the retro-aldol reaction:

Examples of the Grob fragmentation

1) Chem. Rev. 2010, 110, 3741 – 37662)http://www2.chemistry.msu.edu/faculty/reusch/virttxtjml/rearang2.htm

Carbonyl generating Grob fragmentation

Chem. Rev. 2010, 110, 3741 - 3766

Carbonyl generation via ring cleavage reactions:Monosulphanated 1,3,diols:

Basic deprotonation then fragmentation from anion formedForming a lavandulyl system

Stereospecific synthesis of acyclic trisubstituted olefin subunits in cecropia juvenile hormone:

This fragment was built basedon a repetition sequence


Chem. Rev. 2010, 110, 3741 - 3766

In total synthesis:The total synthesis of pallavicinin and neopallavicinin relied on a Grob fragmentation to generate the vinyl moiety in, which is present in both targets:

In total synthesis

This clearly indicates the anti-peri planar arrangement necessary for the Grob fragmentation

Chem. Rev. 2010, 110, 3741 - 3766

Fragmentation from β-hydroxy ketones:

Addition of OH nucleophile to carbonyl followed by fragmentation:Applied to the formation of cis-Chrysanthemic Acid

Β-hydroxy ketones

-OH

O-HO

OMs

In a model system for the synthesis of moenocinol,Grob fragmentation was used to introduce the exomethylenemoiety

Chem. Rev. 2010, 110, 3741 - 3766

Fragmentation can also be induced under different condition to base.LHS shows a reductive mechanism followed by a Grob fragmentationRHS shows a Grignard mediated reaction then it undergoes a Grob

fragmentation

Alternative conditions

Chem. Rev. 2010, 110, 3741 - 3766

Other leaving groups

An example that has the halideleaving 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

Acid catalysed fragmentation

Acid catalysed acetal opening by an antiperi planar arrangement

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.Allylic alcohol was further converted to the esterside chain of disdemnaketal A, a HIV proteaseinhibitor.Chem. Rev. 2010, 110, 3741 - 3766

Carbonyl generation via ring expansion reactions:


Bicyclo[5.4.0]undeconone was synthesised via a ring expanding Grob fragmentation

In the synthesis of parvifoline, a 5,5-ring systemwas used to generate the eight-membered ring When 240 was treated with sodium methoxide under reflux, a Grob fragmentation occurred to form cyclooctenone

Chem. Rev. 2010, 110, 3741 - 3766

Total synthesis

In 2000, in the total synthesis ofcoraxeniolide A wasgenerated by Grob fragmentation. Treatment with sodium hydride led to the unsaturated nine-membered ring .

In 2008, Corey published an enantioselective synthesis ofcaryophyllene . The nine memberedring was generated by fragmentation of diol to dienone. Dienone 258 was also an intermediate in his synthesis of coraxeniolide A.Chem. Rev. 2010, 110, 3741 - 3766

Barans approach to Vinigrol:

Difficult to generate double bond

A fragmentation was used to overcome the inherentring strain of the decahydro-1,5-butanonaphthalene system in intermediate 273.The tetracyclic precursor272 was prepared by two Diels-Alder reactions. Grobfragmentation of monomesylated diol 272 with KHMDS was used to form the tricyclic core

Chem. Rev. 2010, 110, 3741 - 3766

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

Different electrofugal groups

Boronic esters can also be used as electrofugal groups as shown in the e.g. below:

Eschenmosers synthesis 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

Tandem reactions

s leading also to ring opening:

Tandem Semipinacol rearrangement-Grob fragmentation:(a NBS promoted semipinacol rearrangement)Acyclic substrates = a one-step anti-periplanar fragmentationCyclic substrates = a two-step syn-fragmentation

Tandem aldol-Grob fragmentationThe first step was the LA-mediated aldol addition betweenaldehyde and ketone. Next, the newly formed hydroxyl group attacked the activated carbonyl whose fragmentation led to olefin.

Chem. Rev. 2010, 110, 3741 - 3766

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, 4392Heterolyric fragmentation article: Angew.Chem. Int. Ed, 1967, Vol 6, No 1, 1-15 (Grob and Schiess)

The Grob Fragmentation Rachel Atkinson 09.05.12 Special Topic.

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