Recent Developments in AsymmetricCyclopropanation and Applications in Natural Product Synthesis

Angela Udemba a.udemba09@imperial.ac.uk

Overview
Introduction Key cyclopropanation reactions Asymmetric cyclopropanation reactions (chiral auxiliaries and chiral catalysts) Applications in natural product synthesis Conclusion

Introduction
Strained 3-membered ring often displays reactivity similar to that observed for alkenes Manipulation of the cyclopropane ring allows access to synthetic intermediates with tuneable reactivity and stereoselectivity Cyclopropanes are also important subunits in many natural products and biologically important compounds including terpenes, pheromones, fatty acid metabolites and unusual amino acids Since nearly all natural products are chiral, the importance of stereoselectivity in the synthesis of cyclopropanes is well recognised

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

Common Cyclopropanation Reactions 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.

Common Cyclopropanation Reactions 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.

Common Cyclopropanation Reactions

3. Transition metal catalysed decomposition of diazoalkanes

Among the best developed cyclopropanation reactions

Highly effective and stereocontrolled reactions achieved Most common catalysts based on Cu, Rh, and more recently Ru Other 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.

Asymmetric Cyclopropanation
1. Simmons-Smith Reaction
1.1 Chiral auxilaries and directing groups

Chiral auxilaries based on chiral allylic ethers, allylic amines, allylic alcohols, ketals, enamines and enol ethers.

Asymmetric Cyclopropanation
1. Simmons-Smith Reaction
1.1 Chiral auxilaries and directing groups - chiral oxazolidinone derivative
Asymmetric cyclopropanation of aldols

R1 Ph nHex pMeOC6H4 oNO2C6H4 2Fu Me Me H

R2 H H H H H H Me nPent

Yield% 95 89 90 90 92 95 99 96

Chem. Commun., 2005, 2372

Asymmetric Cyclopropanation
1. Simmons-Smith Reaction
1.1 Chiral auxilaries and directing groups
Hydroxy-directed formation of bridged tricyclic diol

Synlett., 2006, 1527

Asymmetric Cyclopropanation
1. Simmons-Smith Reaction
1.1 Chiral auxilaries and directing groups

Tet., 2008, 64, 7041

Asymmetric Cyclopropanation
1. Simmons-Smith Reaction
1.1 Chiral auxilaries and directing groups directing effects of amino alcohols

Aggarwal et al. 2003, the first highly diastereoselective cyclopropanation of allylic amines using Simmons-Smith reagent

Org. Lett., 2003, 5, 4417

Asymmetric Cyclopropanation
1. Simmons-Smith Reaction
1.2. Chiral Catalysts
Many catalytic systems have been reported for stereoselctive Simmons-Smith reaction but very few are used in catalytic amounts Charette et al. 2005 reported the use of chiral phosphoric acid from 3,3disubstituted 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

Asymmetric Cyclopropanation
1. Simmons-Smith Reaction
1.2. Chiral Catalysts
Catalyst 1.2eq Reagents ZnEt2(1.2eq), CH2I2(1.2eq) ZnEt2(1.2eq), CH2I2(1.2eq) Addi3ve 0 %ee >93%

0.1eq

<68%

0.1eq

DME(0.541.2eq) <85% ZnEt2(0.1eq), CH2I2(0.1eq), Zn(CH2I)2(0.9eq)

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

Asymmetric Cyclopropanation
1. Simmons-Smith Reaction
1.2. Chiral Catalysts
To extend substrate scope to both functionalised and unfunctionalised alkenes, the same group also developed a new family of chiral phosphates derived from TADDOL With good to moderate enantioselectivities.

Synth. Catal., 2006, 348, 2363.

Asymmetric Cyclopropanation
1. Simmons-Smith Reaction
1.2. Chiral Catalysts
Other recently reported catalysts used in catalytic amounts are based on chiral disulfonamides,

Tet:Asymmetry, 2006, 17, 3067

Asymmetric Cyclopropanation
1. Simmons-Smith Reaction
1.2. Chiral Catalysts
Other recently reported catalysts used in catalytic amounts are based on chiral disulfonamides, dioxoborolane ligand,

Tet:Asymmetry, 2007, 18, 537

Asymmetric Cyclopropanation
1. Simmons-Smith Reaction
1.2. Chiral Catalysts
Other recently reported catalysts used in catalytic amounts are based on chiral disulfonamides, dioxoborolane ligand, chiral dipeptide

High yields and %ee with stoichiometric amount catalyst.

Tet. Lett., 2005, 46, 13632

Asymmetric Cyclopropanation
1. Simmons-Smith Reaction
1.2. Chiral Catalysts
Other recently reported catalysts used in catalytic amounts are based on chiral disulfonamides, dioxoborolane ligand, chiral dipeptide

%ee significantly reduced with substoichiometric amounts of catalyst Due to background cyclopropanation Addition of achiral additive (EMA) to coordinate zinc and reaction increased %ee with catalytic amount of dipeptide catalyst
Tet. Lett., 2005, 46, 13632

Asymmetric Cyclopropanation
1. Simmons-Smith Reaction
1.2. Chiral Catalysts
Other recently reported catalysts used in catalytic amounts are based on chiral disulfonamides, dioxoborolane ligand, chiral dipeptide and chiral alcohols.

No directing group. Poor enantioselectivity in most cases 51% ee obtained with fructose-derived alcohol
J. Org. Chem., 2004, 69, 327

Asymmetric Cyclopropanation
2. Michael-initiated ring closure
2.1. Chiral Auxilaries

Auxilaries based on chiral nucleophiles for enantioselective and diastereocselective MIRC reaction

Asymmetric Cyclopropanation
2. Michael-initiated ring closure
2.1. Chiral Auxilaries Sulfonium Ylides
Huang et al. 2004 developed camphor derived sulfonium ylide as a chiral nucleophile. High yields (76 91%), des (96 100%) and ees (80 91%) achieved with trans isomer dominant in all cases. Chiral sulfonium ylide also quantitatively recoverable. Enantioselectivity tuned by the choice of base

Synlett, 2005, 1621

Asymmetric Cyclopropanation
2. Michael-initiated ring closure
2.1. Chiral Auxilaries Sulfonium Ylides
Huang et al. 2004 developed camphor derived sulfonium ylide as a chiral nucleophile. High yields (76 91%), des (96 100%) and ees (80 91%) achieved with trans isomer dominant in all cases. Chiral sulfonium ylide also quantitatively recoverable. Enantioselectivity tuned by the choice of base

Reaction scope extended to the use of acrylonitrile as the electrophile Synlett, 2005, 1621

Asymmetric Cyclopropanation
2.1. Chiral Auxilaries - nitrigen ylides

2. Michael-initiated ring closure

Relatively few examples of nitrogen-derived ylides in literature Yamada et al recently reported the application of chiral pyridinium ylide for asymmetric cyclopropantion of electron-deficient alkenes. Auxilary conformation fixed through a cation- interaction

Tet. Lett., 2007, 48, 855

Asymmetric Cyclopropanation
2.1. Chiral Auxilaries - nitrigen ylides

2. Michael-initiated ring closure

Relatively few examples of nitrogen-derived ylides in literature Yamada et al recently reported the application of chiral pyridinium ylide for asymmetric cyclopropanation of electron-deficient alkenes. Auxilary conformation fixed through a cation- interaction

Tet. Lett., 2007, 48, 855

Asymmetric Cyclopropanation
2. Michael-initiated ring closure
2.2. Chiral Catalysts
Recent development of chiral organocatalysts for MIRC cyclopropanation reactions First example of the use of chiral ammonium ylide as an organocatalyst reported in 2003

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

Asymmetric Cyclopropanation
2. Michael-initiated ring closure
2.2. Chiral Catalysts
Recent development of chiral organocatalysts for MIRC cyclopropanation reactions First example of the use of chiral ammonium ylide as an organocatalyst reported in 2003

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

Asymmetric Cyclopropanation
2. Michael-initiated ring closure
2.2. Chiral Catalysts
Scope extended to intramolecular reactions and cyclopropanation between halomethyl ketones and malonitriles

Tet., 2008, 64, 7041

Asymmetric Cyclopropanation
3. Transition metal mediated decomposition of diazoalkanes
3.1. Chiral Auxilaries
Cyclopropanation of styrene with ethyl diazoacetate (EDA) often used as bench-mark reaction for evaluation of almost any new catalyst/auxilary. Very few chiral auxilaries developed for cyclopropanation by decomposition of diazoalkanes. Several carbohydrates employed as auxilaries for asymmetric cyclopropanation The few examples of their use in Cu catalysed reactions of alkenes generally show low des and ees.

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

Asymmetric Cyclopropanation
3. Transition metal mediated decomposition of diazoalkanes
3.1. Chiral Auxilaries
Ferreira et al. 2007 reported the simultaneous use of carbohydrate-derived auxilaries and chiral cu(I) ligand to induce chirality. Studies showed the importance of the auxilary on enantioselectivities and cis/trans ratios.
Auxilary 2a 2b 2c 2d 2e Yield% 30 25 62 35 15 de% 90 60 50 92 70 ee(trans) ee(cis)% % 53 60 26 19 <10 <10 2 34 92 2

Tet:Asymmetry, 2007, 18, 1217

Asymmetric Cyclopropanation
3. Transition metal mediated decomposition of diazoalkanes
3.2. Chiral Copper catalysts bisoxazolidine ligands
Cu catalysed cyclopropanation reactions particularly well established With chiral C2 symmetric bidentate bisoxazolidine ligands as by far the most widely used chiral Cu ligands Ligand structure has a strong influence on stereoselectivity where even very small changes often have drastic and unpredictable effects on enantioselectivities

Tet., 2008, 64, 7041

Asymmetric Cyclopropanation
3. Transition metal mediated decomposition of diazoalkanes
3.2. Chiral Rhodium catalysts
A number of chiral catalysts have been applied to the Rh-catalysed cyclopropanation Naphthanoyl ligand below is an example of a recently developed effective Rh ligand for 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

Asymmetric Cyclopropanation
3. Transition metal mediated decomposition of diazoalkanes
3.2. Chiral Rhodium catalysts
Owing to the importance of fluorine substituents on the properties of organic compounds, Davies et al. described the formation of trifluoromethyl substituted cyclopropanes in high yield, ees and des Using adamantyl derived dirhodium complex

Org. Lett., 2007, 9, 2625

Asymmetric Cyclopropanation
3. Transition metal mediated decomposition of diazoalkanes
3.2. Chiral Rhodium catalysts
Davies et al. also described the use of dirhodium tetrakis ligand Rh2[(R)-DOSP]4 complex 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

Asymmetric Cyclopropanation
3. Transition metal mediated decomposition of diazoalkanes
3.2. Chiral Ruthenium catalysts
Ruthenium complexes more recently introduced in the field of catalytic cyclopropanation Ruthenium complexes offer alternatives to the much more expensive rhodium metal Ruthenium also offers greater diversity of complexes to be evaluated due to the higher number of oxidation states However, a limitation of ruthenium complexes is the relatively low electrophilicity of the Ru-carbene intermediate Restricting applications to terminal activated alkenes and double bonds with higher degree of alkyl substitution. Ru also catalyses competing reactions such as metathesis and alkene homologation
Tet., 2008, 64, 7041

Asymmetric Cyclopropanation
3. Transition metal mediated decomposition of diazoalkanes
3.2. Chiral Ruthenium catalysts
Several diphosphines have been used as ruthenium ligands to catalyse cyclopropanations e.g. [RuCl(PNNP)]+SbF6- with ee of up to 98%

PNNP ligand
Tet:Asymmetry, 2003, 14, 845

Asymmetric Cyclopropanation
3. Transition metal mediated decomposition of diazoalkanes
3.2. Chiral Ruthenium catalysts
Several recent reports on the use of ruthenium porphyrin catalysts for the cyclopropanation of alkenes Providing up to 92% ee and 98% de with high yields

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

Heterocycles from Cyclopropanes: Cyclopropane ringexpansion reactions in natural product synthesis

Ring expansion of cyclopropanes emerging as rapid and versatile methods for the synthesis 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

Heterocycles from Cyclopropanes: Cyclopropane ringexpansion reactions in natural product synthesis 1. MgI2 catalysed ring-expansion reactions
Reaction of spirocyclopropane-1,3-oxindoles with imines results in formation of spirofused pyrrolidines naturally occurring molecules with biological activities.

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

Heterocycles from Cyclopropanes: Cyclopropane ringexpansion reactions in natural product synthesis 1. MgI2 catalysed ring-expansion reactions
Magnesium iodide catalysts acts as both nucleophile and the electrophile in the first step. Pathway A is the preferred method

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

Heterocycles from Cyclopropanes: Cyclopropane ringexpansion reactions in natural product synthesis 2. Reaction of nitrones and cyclopropanes Tetrahydro-1,2-oxazines

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

Heterocycles from Cyclopropanes: Cyclopropane ringexpansion reactions in natural product synthesis 2. Reaction of nitrones and cyclopropanes Tetrahydro-1,2-oxazines
Highly regioselective reaction with nucleophilic attack at the cyclopropane position best able to stabilise a developing positive charge Products often obtained as single stereoisomers bearing a cis relationship between their C3 and C6 substituents Nitrones prepared in situ through condensation of an aldehyde with a hydroxylamine

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

Heterocycles from Cyclopropanes: Cyclopropane ringexpansion reactions in natural product synthesis 3. Intramolecular oxime ether annulations Pyrrolo-isoxazolidines
Preparation of pyrrolo-oxazolidines via intramolecular annulation reaction of a cyclopropane and an oxime ether.

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

Heterocycles from Cyclopropanes: Cyclopropane ringexpansion reactions in natural product synthesis 3. Intramolecular oxime ether annulations Pyrrolo-isoxazolidines
Preparation of pyrrolo-oxazolidines via intramolecular annulation reaction of a cyclopropane and an oxime ether Intramolecular process exceptionally facile and highly stereoselective Inversion of configuration observed at the chiral cyclopropane centre

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

Heterocycles from Cyclopropanes: Cyclopropane ringexpansion reactions in natural product synthesis 3. Intramolecular oxime ether annulations Pyrrolo-isoxazolidines
Relative stereochemical outcome across the pyrrolidine ring can be tuned by reaction pathway The cis/trans relationship found governed by the E/Z geometry of the oxime ether Treatment of the E-oxime ethers with a Lewis acid results in trans pyrroloisoxazolidines 43

Heterocycles from Cyclopropanes: Cyclopropane ringexpansion reactions in natural product synthesis 3. Intramolecular oxime ether annulations Pyrrolo-isoxazolidines
Z-oximes found to give rise to exclusively cis-isoxazolidines 47 Z-oximes obtained as minor isomers (if formed at all) from condensation of aldehydes with alkoxyamine 41.

Heterocycles from Cyclopropanes: Cyclopropane ringexpansion reactions in natural product synthesis 3. Intramolecular oxime ether annulations Pyrrolo-isoxazolidines
Thus cis isomer easily accessed by changing the order of addition of the aldehyde and Lewis acid.

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/ natural product synthesis