Asymmetric Cyclopropanation Seminar 090611

8/22/2019 Asymmetric Cyclopropanation Seminar 090611

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Recent Developments inAsymmetricCyclopropanation andApplications in Natural Product Synthesis

Angela Udemba

[email protected]


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Overview

Introduction Key cyclopropanation reactions Asymmetric cyclopropanation reactions (chiral auxiliaries and chiral

catalysts)

Applications in natural product synthesis Conclusion


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Introduction

Strained 3-membered ring often displays reactivity similar to that observed foralkenes

Manipulation of the cyclopropane ring allows access to synthetic intermediates withtuneable reactivity and stereoselectivity

Cyclopropanes are also important subunits in many natural products and biologicallyimportant compounds including terpenes, pheromones, fatty acid metabolites and

unusual amino acids

Since nearly all natural products are chiral, the importance of stereoselectivity in thesynthesis of cyclopropanes is well recognised


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Common Cyclopropanation Reactions

1. Simmons-Smith Cyclopropanation

Reactive intermediate - RZnCH2I, prepared using ZnEt2 or Zn/Cu and CH2I2

- Broad substrate scope

- Tolerance of a variety of functional groups

- Stereospecificity with respect to alkene geometry


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1. Simmons-Smith Cyclopropanation

- Stereospecificity with respect to alkene geometry

- Syn-directing/ rate-enhancing (>1000-fold)effect observed with proximal oxygen atoms

J. Am. Chem. Soc., 1958, 80, 5323; Tet., 1987, 43, 2203; Chem. Rev., 1996, 96,49; Synlett, 1995, 1197.


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2. Michael Initiated Ring Closure

In general MIRC reactions with acyclic olefins are nonstereospecific with both (E)-and (Z)-olefins giving the corresponding trans cyclopropane

Stereospecific MIRC reactions observed only when ring closure is faster than the

rotation around the single bond in the intermediate

Tet., 2008, 64, 7041; Angew. Chem., 2006, 118, 6170; Angew. Chem., 2004, 116,4741; J. Am. Chem. Soc., 2005, 127, 3240.


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Common Cyclopropanation Reactions3. Transition metal catalysed decomposition of diazoalkanes

Among the best developed cyclopropanation reactionsHighly effective and stereocontrolled reactions achievedMost common catalysts based on Cu, Rh, and more recently RuOther catalysts based on Pd, Os, and Fe reported only occassionally

Tet., 2008, 64, 7041; Org. React., 2001, 57, 1; Inorg. Chem., 2001, 50, 1;Chem. Rev., 1998, 69, 122.


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Asymmetric Cyclopropanation

1. Simmons-Smith Reaction

Chiral auxilaries based on chiral allylic ethers, allylic amines, allylic alcohols, ketals,

enamines and enol ethers.

1.1 Chiral auxilaries and directing groups


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Asymmetric cyclopropanation of aldols

1.1 Chiral auxilaries and directing groups - chiral oxazolidinone derivative

R1 R2 Yield %

Ph H 95

nHex H 89

pMeOC6H4 H 90

oNO2C6H4 H 90

2Fu H 92

Me H 95

Me Me 99

H nPent 96

Chem. Commun., 2005, 2372


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Hydroxy-directed formation of bridged tricyclic diol

1.1 Chiral auxilaries and directing groups

Synlett., 2006, 1527


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1. Simmons-Smith Reaction1.1 Chiral auxilaries and directing groups

Tet., 2008, 64, 7041


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1. Simmons-Smith Reaction1.1 Chiral auxilaries and directing groups directing effects of amino alcohols

Org. Lett., 2003, 5, 4417

Aggarwal et al. 2003, the first highly diastereoselective cyclopropanation of allylic

amines using Simmons-Smith reagent


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1. Simmons-Smith Reaction1.2. Chiral Catalysts

Many catalytic systems have been reported for stereoselctive Simmons-Smithreaction but very few are used in catalytic amounts

Charette et al. 2005 reported the use of chiral phosphoric acid from 3,3-disubstituted BINOL to design a chiral zinc phosphate reagent used in catalytic

amounts

For the cyclopropanation of allylic alcohols and ethers

J. Am. Chem Soc., 2005, 127, 12440


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Catalyst Reagents Addi3ve % ee

1.2 eq ZnEt2 (1.2 eq),

CH2I2 (1.2 eq)

0 >93%

0.1 eq ZnEt2 (1.2 eq),

CH2I2 (1.2 eq)

0


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To extend substrate scope to both functionalised and unfunctionalised alkenes, thesame group also developed a new family of chiral phosphates derived from TADDOL

With good to moderate enantioselectivities.

Synth. Catal., 2006, 348, 2363.


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Other recently reported catalysts used in catalytic amounts are based onchiral disulfonamides,

Tet:Asymmetry, 2006, 17, 3067


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Other recently reported catalysts used in catalytic amounts are based onchiral disulfonamides, dioxoborolane ligand,



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Other recently reported catalysts used in catalytic amounts are based on chiraldisulfonamides, dioxoborolane ligand, chiral dipeptide

High yields and %ee with stoichiometric amountcatalyst.

Tet. Lett., 2005, 46, 13632


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Other recently reported catalysts used in catalytic amounts are based on chiraldisulfonamides, dioxoborolane ligand, chiral dipeptide

%ee significantly reduced with substoichiometricamounts of catalyst

Due to background cyclopropanationAddition of achiral additive (EMA) to coordinatezinc and reaction increased %ee with catalytic

amount of dipeptide catalyst

Tet. Lett., 2005, 46, 13632


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Other recently reported catalysts used in catalytic amounts are based on chiraldisulfonamides, dioxoborolane ligand, chiral dipeptide and chiralalcohols.

J. Org. Chem., 2004, 69, 327

No directing group.Poor enantioselectivity in most cases51% ee obtained with fructose-derived alcohol


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2. Michael-initiated ring closure2.1. Chiral Auxilaries

Auxilaries based on chiral nucleophiles for enantioselective and diastereocselectiveMIRC reaction


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2. Michael-initiated ring closure2.1. Chiral Auxilaries Sulfonium Ylides

Huang et al. 2004 developed camphor derived sulfonium ylide as a chiralnucleophile.

High yields (76 91%), des (96 100%) and ees (80 91%) achieved with transisomer dominant in all cases.

Chiral sulfonium ylide also quantitatively recoverable.Enantioselectivity tuned by the choice of base

Synlett, 2005, 1621


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2. Michael-initiated ring closure2.1. Chiral Auxilaries Sulfonium Ylides

Huang et al. 2004 developed camphor derived sulfonium ylide as a chiralnucleophile.

High yields (76 91%), des (96 100%) and ees (80 91%) achieved with transisomer dominant in all cases.

Chiral sulfonium ylide also quantitatively recoverable.Enantioselectivity tuned by the choice of base

Synlett, 2005, 1621

Reaction scope extended to the use of acrylonitrile as the electrophile


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2. Michael-initiated ring closure2.1. Chiral Auxilaries - nitrigen ylides

Relatively few examples of nitrogen-derived ylides in literatureYamada et al recently reported the application of chiral pyridinium ylide for asymmetriccyclopropantion of electron-deficient alkenes.

Auxilary conformation fixed through a cation- interaction

Tet. Lett., 2007, 48, 855


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2. Michael-initiated ring closure2.1. Chiral Auxilaries - nitrigen ylides

Relatively few examples of nitrogen-derived ylides in literatureYamada et al recently reported the application of chiral pyridinium ylide for asymmetriccyclopropanation of electron-deficient alkenes.

Auxilary conformation fixed through a cation- interaction

Tet. Lett., 2007, 48, 855


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2. Michael-initiated ring closure2.2. Chiral Catalysts

Recent development of chiral organocatalysts for MIRC cyclopropanation reactionsFirst example of the use of chiral ammonium ylide as an organocatalyst reported in2003

Angew. chem. Int. Ed., 2004, 43, 4641


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Recent development of chiral organocatalysts for MIRC cyclopropanation reactionsFirst example of the use of chiral ammonium ylide as an organocatalyst reported in2003

Angew. chem. Int. Ed., 2004, 43, 4641


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Scope extended to intramolecular reactions and cyclopropanation betweenhalomethyl ketones and malonitriles

Tet., 2008, 64, 7041


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3. Transition metal mediated decomposition of diazoalkanes3.1. Chiral Auxilaries

Cyclopropanation of styrene with ethyl diazoacetate (EDA) often used as bench-markreaction for evaluation of almost any new catalyst/auxilary.

Very few chiral auxilaries developed for cyclopropanation by decomposition ofdiazoalkanes.Several carbohydrates employed as auxilaries for asymmetric cyclopropanationThe few examples of their use in Cu catalysed reactions of alkenes generally showlow des and ees.

Coord. Chem. Rev., 2004, 248, 2165


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3. Transition metal mediated decomposition of diazoalkanes3.1. Chiral Auxilaries

Ferreira et al. 2007 reported the simultaneous use of carbohydrate-derivedauxilaries and chiral cu(I) ligand to induce chirality.

Studies showed the importance of the auxilary on enantioselectivities and cis/transratios.


Auxilary Yield % de % ee(trans)

%

ee (cis) %

2a 30 90 60 53

2b 25 60 19 26

2c 62 50 < 10 < 10

2d 35 92 34 2

2e 15 70 2 92


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3. Transition metal mediated decomposition of diazoalkanes3.2. Chiral Copper catalysts bisoxazolidine ligands

Cu catalysed cyclopropanation reactions particularly well establishedWith chiral C2 symmetric bidentate bisoxazolidine ligands as by far the most widelyused chiral Cu ligands

Ligand structure has a strong influence on stereoselectivity where even very smallchanges often have drastic and unpredictable effects on enantioselectivities

Tet., 2008, 64, 7041


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3. Transition metal mediated decomposition of diazoalkanes3.2. Chiral Rhodium catalysts

A number of chiral catalysts have been applied to the Rh-catalysed cyclopropanationNaphthanoyl ligand below is an example of a recently developed effective Rh ligandfor asymmetric cyclopropanation.

Reaction scope extended to cyclopropanation of alkenes like dihydrofuran and

dihydropyran with very high yields, ees and des

Org. Lett., 2004, 6, 1725


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Owing to the importance of fluorine substituents on the properties of organiccompounds,

Davies et al. described the formation of trifluoromethyl substituted cyclopropanes inhigh yield, ees and des

Using adamantyl derived dirhodium complex

Org. Lett., 2007, 9, 2625


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Davies et al. also described the use of dirhodium tetrakis ligand Rh2[(R)-DOSP]4complex to induce the decomposition of aryldiazoacetates in the presence of furans and

pyrroles

Resulting in mono- or biscyclopropanes of the heterocycle but with opposite

enatioinduction with high yield and ees (> 95%)

J. Org. Chem., 2006, 71, 5356


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3. Transition metal mediated decomposition of diazoalkanes3.2. Chiral Ruthenium catalysts

Ruthenium complexes more recently introduced in the field of catalyticcyclopropanation

Ruthenium complexes offer alternatives to the much more expensive rhodium metalRuthenium also offers greater diversity of complexes to be evaluated due to thehigher number of oxidation states

However, a limitation of ruthenium complexes is the relatively low electrophilicity of theRu-carbene intermediate

Restricting applications to terminal activated alkenes and double bonds with higherdegree of alkyl substitution.

Ru also catalyses competing reactions such as metathesis and alkene homologationTet., 2008, 64, 7041


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Several diphosphines have been used as ruthenium ligands to catalysecyclopropanations

e.g. [RuCl(PNNP)]+SbF6- with ee of up to 98%


PNNP ligand


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Several recent reports on the use of ruthenium porphyrin catalysts for thecyclopropanation of alkenes

Providing up to 92% ee and 98% de with high yields

Chem.-Eur. J., 2003, 9, 4746; Org. Lett., 2004, 6, 3211


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Heterocycles from Cyclopropanes: Cyclopropane ring-expansion reactions in natural product synthesis

Ring expansion of cyclopropanes emerging as rapid and versatile methods for thesynthesis of a variety of complex heterocyclic systems.

Array of dipolar reagents (e.g. aldehydes, imines, nitrones, diazenes, nitriles,azomethine imines etc.) readily react with cyclopropanes to give 5 6 membered

heterocyclic rings

Chem. Soc. Rev., 2009, 38, 3051


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Reaction of spirocyclopropane-1,3-oxindoles with imines results in formation ofspirofused pyrrolidines naturally occurring molecules with biological activities.

1. MgI2 catalysed ring-expansion reactions

Chem. Soc. Rev., 2009, 38, 3051


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Magnesium iodide catalysts acts as both nucleophile and the electrophile in the firststep.

Pathway A is the preferred method

1. MgI2 catalysed ring-expansion reactions

Chem. Soc. Rev., 2009, 38, 3051


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2. Reaction of nitrones and cyclopropanes Tetrahydro-1,2-oxazines

Chem. Soc. Rev., 2009, 38, 3051


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Highly regioselective reaction with nucleophilic attack at the cyclopropane positionbest able to stabilise a developing positive charge

Products often obtained as single stereoisomers bearing a cis relationship betweentheir C3 and C6 substituents

Nitrones prepared in situ through condensation of an aldehyde with a hydroxylamine

2. Reaction of nitrones and cyclopropanes Tetrahydro-1,2-oxazines

Chem. Soc. Rev., 2009, 38, 3051


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Preparation of pyrrolo-oxazolidines via intramolecular annulation reaction of acyclopropane and an oxime ether.

3. Intramolecular oxime ether annulations Pyrrolo-isoxazolidines

Chem. Soc. Rev., 2009, 38, 3051


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Preparation of pyrrolo-oxazolidines via intramolecular annulation reaction of acyclopropane and an oxime ether

Intramolecular process exceptionally facile and highly stereoselectiveInversion of configuration observed at the chiral cyclopropane centre


Chem. Soc. Rev., 2009, 38, 3051


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Relative stereochemical outcome across the pyrrolidine ring can be tuned by reactionpathwayThe cis/trans relationship found governed by the E/Z geometry of the oxime etherTreatment of the E-oxime ethers with a Lewis acid results in trans pyrrolo-isoxazolidines 43



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Z-oximes found to give rise to exclusively cis-isoxazolidines 47Z-oximes obtained as minor isomers (if formed at all) from condensation of aldehydeswith alkoxyamine 41.



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Thus cis isomer easily accessed by changing the order of addition of the aldehydeand Lewis acid.


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Summary

The use of chiral auxilaries and chiral catalysts in 3 key cyclopropanation reactions:Simmons-Smith reaction

Michael-initiated ring closure

Transition metal catalysed decomposition of diazoalkanes using Cu, Rh, Ru

Applications of cyclopropane ring expansion in synthesis of heterocycles/ naturalproduct synthesis

Asymmetric Cyclopropanation Seminar 090611

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