Download - Asymmetric Cyclopropanation Seminar 090611
-
8/22/2019 Asymmetric Cyclopropanation Seminar 090611
1/48
Recent Developments inAsymmetricCyclopropanation andApplications in Natural Product Synthesis
Angela Udemba
-
8/22/2019 Asymmetric Cyclopropanation Seminar 090611
2/48
Overview
Introduction Key cyclopropanation reactions Asymmetric cyclopropanation reactions (chiral auxiliaries and chiral
catalysts)
Applications in natural product synthesis Conclusion
-
8/22/2019 Asymmetric Cyclopropanation Seminar 090611
3/48
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
-
8/22/2019 Asymmetric Cyclopropanation Seminar 090611
4/48
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
-
8/22/2019 Asymmetric Cyclopropanation Seminar 090611
5/48
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.
-
8/22/2019 Asymmetric Cyclopropanation Seminar 090611
6/48
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.
-
8/22/2019 Asymmetric Cyclopropanation Seminar 090611
7/48
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.
-
8/22/2019 Asymmetric Cyclopropanation Seminar 090611
8/48
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
-
8/22/2019 Asymmetric Cyclopropanation Seminar 090611
9/48
Asymmetric Cyclopropanation
1. Simmons-Smith Reaction
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
-
8/22/2019 Asymmetric Cyclopropanation Seminar 090611
10/48
Asymmetric Cyclopropanation
1. Simmons-Smith Reaction
Hydroxy-directed formation of bridged tricyclic diol
1.1 Chiral auxilaries and directing groups
Synlett., 2006, 1527
-
8/22/2019 Asymmetric Cyclopropanation Seminar 090611
11/48
Asymmetric Cyclopropanation
1. Simmons-Smith Reaction1.1 Chiral auxilaries and directing groups
Tet., 2008, 64, 7041
-
8/22/2019 Asymmetric Cyclopropanation Seminar 090611
12/48
Asymmetric Cyclopropanation
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
-
8/22/2019 Asymmetric Cyclopropanation Seminar 090611
13/48
Asymmetric Cyclopropanation
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
-
8/22/2019 Asymmetric Cyclopropanation Seminar 090611
14/48
Asymmetric Cyclopropanation
1. Simmons-Smith Reaction1.2. Chiral Catalysts
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
-
8/22/2019 Asymmetric Cyclopropanation Seminar 090611
15/48
Asymmetric Cyclopropanation
1. Simmons-Smith Reaction1.2. Chiral Catalysts
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.
-
8/22/2019 Asymmetric Cyclopropanation Seminar 090611
16/48
Asymmetric Cyclopropanation
1. Simmons-Smith Reaction1.2. Chiral Catalysts
Other recently reported catalysts used in catalytic amounts are based onchiral disulfonamides,
Tet:Asymmetry, 2006, 17, 3067
-
8/22/2019 Asymmetric Cyclopropanation Seminar 090611
17/48
Asymmetric Cyclopropanation
1. Simmons-Smith Reaction1.2. Chiral Catalysts
Other recently reported catalysts used in catalytic amounts are based onchiral disulfonamides, dioxoborolane ligand,
Tet:Asymmetry, 2007, 18, 537
-
8/22/2019 Asymmetric Cyclopropanation Seminar 090611
18/48
Asymmetric Cyclopropanation
1. Simmons-Smith Reaction1.2. Chiral Catalysts
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
-
8/22/2019 Asymmetric Cyclopropanation Seminar 090611
19/48
Asymmetric Cyclopropanation
1. Simmons-Smith Reaction1.2. Chiral Catalysts
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
-
8/22/2019 Asymmetric Cyclopropanation Seminar 090611
20/48
Asymmetric Cyclopropanation
1. Simmons-Smith Reaction1.2. Chiral Catalysts
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
-
8/22/2019 Asymmetric Cyclopropanation Seminar 090611
21/48
Asymmetric Cyclopropanation
2. Michael-initiated ring closure2.1. Chiral Auxilaries
Auxilaries based on chiral nucleophiles for enantioselective and diastereocselectiveMIRC reaction
-
8/22/2019 Asymmetric Cyclopropanation Seminar 090611
22/48
Asymmetric Cyclopropanation
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
-
8/22/2019 Asymmetric Cyclopropanation Seminar 090611
23/48
Asymmetric Cyclopropanation
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
-
8/22/2019 Asymmetric Cyclopropanation Seminar 090611
24/48
Asymmetric Cyclopropanation
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
-
8/22/2019 Asymmetric Cyclopropanation Seminar 090611
25/48
Asymmetric Cyclopropanation
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
-
8/22/2019 Asymmetric Cyclopropanation Seminar 090611
26/48
Asymmetric Cyclopropanation
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
-
8/22/2019 Asymmetric Cyclopropanation Seminar 090611
27/48
Asymmetric Cyclopropanation
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
-
8/22/2019 Asymmetric Cyclopropanation Seminar 090611
28/48
Asymmetric Cyclopropanation
2. Michael-initiated ring closure2.2. Chiral Catalysts
Scope extended to intramolecular reactions and cyclopropanation betweenhalomethyl ketones and malonitriles
Tet., 2008, 64, 7041
-
8/22/2019 Asymmetric Cyclopropanation Seminar 090611
29/48
Asymmetric Cyclopropanation
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
-
8/22/2019 Asymmetric Cyclopropanation Seminar 090611
30/48
Asymmetric Cyclopropanation
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.
Tet:Asymmetry, 2007, 18, 1217
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
-
8/22/2019 Asymmetric Cyclopropanation Seminar 090611
31/48
Asymmetric Cyclopropanation
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
-
8/22/2019 Asymmetric Cyclopropanation Seminar 090611
32/48
Asymmetric Cyclopropanation
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
-
8/22/2019 Asymmetric Cyclopropanation Seminar 090611
33/48
Asymmetric Cyclopropanation
3. Transition metal mediated decomposition of diazoalkanes3.2. Chiral Rhodium catalysts
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
-
8/22/2019 Asymmetric Cyclopropanation Seminar 090611
34/48
Asymmetric Cyclopropanation
3. Transition metal mediated decomposition of diazoalkanes3.2. Chiral Rhodium catalysts
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
-
8/22/2019 Asymmetric Cyclopropanation Seminar 090611
35/48
Asymmetric Cyclopropanation
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
-
8/22/2019 Asymmetric Cyclopropanation Seminar 090611
36/48
Asymmetric Cyclopropanation
3. Transition metal mediated decomposition of diazoalkanes3.2. Chiral Ruthenium catalysts
Several diphosphines have been used as ruthenium ligands to catalysecyclopropanations
e.g. [RuCl(PNNP)]+SbF6- with ee of up to 98%
Tet:Asymmetry, 2003, 14, 845
PNNP ligand
-
8/22/2019 Asymmetric Cyclopropanation Seminar 090611
37/48
Asymmetric Cyclopropanation
3. Transition metal mediated decomposition of diazoalkanes3.2. Chiral Ruthenium catalysts
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
-
8/22/2019 Asymmetric Cyclopropanation Seminar 090611
38/48
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
-
8/22/2019 Asymmetric Cyclopropanation Seminar 090611
39/48
Heterocycles from Cyclopropanes: Cyclopropane ring-expansion reactions in natural product synthesis
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
-
8/22/2019 Asymmetric Cyclopropanation Seminar 090611
40/48
Heterocycles from Cyclopropanes: Cyclopropane ring-expansion reactions in natural product synthesis
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
-
8/22/2019 Asymmetric Cyclopropanation Seminar 090611
41/48
Heterocycles from Cyclopropanes: Cyclopropane ring-expansion reactions in natural product synthesis
2. Reaction of nitrones and cyclopropanes Tetrahydro-1,2-oxazines
Chem. Soc. Rev., 2009, 38, 3051
-
8/22/2019 Asymmetric Cyclopropanation Seminar 090611
42/48
Heterocycles from Cyclopropanes: Cyclopropane ring-expansion reactions in natural product synthesis
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
-
8/22/2019 Asymmetric Cyclopropanation Seminar 090611
43/48
Heterocycles from Cyclopropanes: Cyclopropane ring-expansion reactions in natural product synthesis
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
-
8/22/2019 Asymmetric Cyclopropanation Seminar 090611
44/48
Heterocycles from Cyclopropanes: Cyclopropane ring-expansion reactions in natural product synthesis
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
3. Intramolecular oxime ether annulations Pyrrolo-isoxazolidines
Chem. Soc. Rev., 2009, 38, 3051
-
8/22/2019 Asymmetric Cyclopropanation Seminar 090611
45/48
Heterocycles from Cyclopropanes: Cyclopropane ring-expansion reactions in natural product synthesis
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
3. Intramolecular oxime ether annulations Pyrrolo-isoxazolidines
-
8/22/2019 Asymmetric Cyclopropanation Seminar 090611
46/48
Heterocycles from Cyclopropanes: Cyclopropane ring-expansion reactions in natural product synthesis
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.
3. Intramolecular oxime ether annulations Pyrrolo-isoxazolidines
-
8/22/2019 Asymmetric Cyclopropanation Seminar 090611
47/48
Heterocycles from Cyclopropanes: Cyclopropane ring-expansion 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 aldehydeand Lewis acid.
-
8/22/2019 Asymmetric Cyclopropanation Seminar 090611
48/48
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