Cyclopropane Strain - James Madison University

Cyclopropane Strain - James Madison University

A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005 Outline I. Introduction to Cyclopropanes and Heterocycle Formation Strategies II. Proof of Concept: Oxepane Synthesis III. Progress Towards Nitrogenous Heterocycles IV. Radical Strategies V. Future Directions Outline I. Introduction to Cyclopropanes and Heterocycle Formation Strategies II. Proof of Concept: Oxepane Synthesis III. Progress Towards Nitrogenous Heterocycles IV. Radical Strategies V. Future Directions Cyclopropane Strain and Reactivity Cyclopropane has significant ring strain. Ring Strain ~ 27.5 kcal/mol Cyclopropanes have pi character. Coulson-Moffitt Model Bent Bonds

Walsh Model Alkenes and Cyclopropanes Virtually every reaction that an alkene undergoes has its counterpart in the repertoire of transformations possible with cyclopropanes. Reactivity towards electrophiles Reactivity towards nucleophiles O Nu O Nu O Nu Nu H O + E O O

O E H O + E E Hudlicky, T.; Reed, J. W. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I. Eds.; Pergamon: Oxford, 1991; Vol. 5, p 901. Alkenes and Cyclopropanes Carreiras approach to spirotryprostatin B I O I N O N Bn MgI2 R N OMgI

N R O R O N Bn N R R R Cossys approach to zincophorin Hg(OTf)2; O BzO H OH OH O O BzO KBr

H O H 85% OH HgBr H3CO H O O N H spirotryprostatin B N Bn N Bn N H O H zincophorin

Marti, C.; Carreira, E. M. J. Am. Chem. Soc. 2005, ASAP. Cossy, J.; Blanchard, N.; Defosseux, M.; Meyer, C. Angew. Chem. Int. Ed. 2002, 41, 2144. OH Alkenes and Cyclopropanes Reactivity towards electrophiles O H O E O + E H O E + E Could this be used to generate heterocycles? O H O +

E E Oxocarbenium-Based Heterocycle Syntheses X LA OH X RCHO O Prins O O O O LA O O LA O Prins-Pinacol O O

O LA O LA O O O O Petasis O LA O H LA O O O LA This work O Analogous modes of cyclization O

Zimmerman-Traxler Cyclization O O LA O R O O R R O R LA R R Petasis R R H R O O

R O O LA LA R O O MO R OH OH R O MO This work R R H O OH OH Initial target

R The Kulinkovich Cyclopropanation O R1 Kulinkovich Reaction OR2 R1 Ti(O-iPr)4 (0.1 eq) EtMgBr (3 eq) THF/Et2O (4:1) OH R Ti(OR)4 + 2 EtMgBr RO RO H3C CH3 RO Ti RO RO Ti

RO Ti RO RO Ti R O R XMgO R EtMgBr RO RO O Ti R EtMgBr RO RO Ti O OR R OR Kulinkovich, O. G. Chem. Rev. 2003, 103, 2597.

XMgO R R Cyclopropanation Yields O O Ti(O-iPr)4 (0.1 eq) EtMgBr (3 eq) THF/Et2O (4:1) <30% OH OH O Ti(O-iPr)4 (0.1 eq) EtMgBr (3 eq) THF/Et2O (4:1) 80% O OH O OEt TiCl(O-iPr)3 (1 eq) EtMgBr (4 eq) THF/Et2O (4:1) 51% OEt TiCl(O-iPr)3 (1 eq)

EtMgBr (4 eq) THF/Et2O (4:1) 51% OH O OH OH OH OH OH OH Cho, S. Y.; Cha, J. K. Org. Lett. 2000, 2, 1337-1339. Outline I. Introduction to Cyclopropanes and Heterocycle Formation Strategies II. Proof of Concept: Oxepane Synthesis III. Progress Towards Nitrogenous Heterocycles IV. Radical Strategies V. Future Directions Initial Attempts at Oxepane Formation PhCHO, Na2SO4 CH2Cl2, 0.1M OH OH M(OTf)3, -78 oC M = Al, Bi, In

O O Ph Initial Attempts at Oxepane Formation O PhCHO, Na2SO4 CH2Cl2, 0.1M OH OH M(OTf)3, -78 oC M = Al, Bi, In warm to O O Ph 0 oC O 30-50% Softer Lewis acids (CuSO4, ZnCl2, SnCl2) stop at acetal Ph Mechanism of Oxepane Formation

PhCHO, Na2SO4 CH2Cl2, 0.1M OH OH Al(OTf)3 0 oC O O O Ph O LA Ph O LA O O Ph O Ph Mechanism of Oxepane Formation PhCHO, Na2SO4 CH2Cl2, 0.1M

OH OH Al(OTf)3 0 oC OH OH O O O Ph LA O Ph LA O PhCHO, Na2SO4 CH2Cl2, 0.1M Al(OTf)3 0 oC O O Ph O

Ph LA O - PhCHO O Ph O LA O Ph Ph O Ph Ph Ph O 69% Stereochemistry of Oxepane Formation O PhCHO, Na2SO4 CH2Cl2, 0.1M OH OH

M(OTf)3, -78 oC warm to O O Ph 0 oC M = Al, Bi, In O O H O H Ph 10% nOe H O H Ph 10% nOe O Ph

30-50% Zimmerman-Traxler Cyclization O O LA O R O R R O R R O MO R R O R Initial Limitations of Oxepane Formation O PhCHO, Na2SO4

CH2Cl2, 0.1M OH OH M(OTf)3, -78 oC M = Al, Bi, In warm to O O 0 oC Ph O Ph 30-50% O O H O H Ph H O PhCH2CH2CHO,

Na2SO4 CH2Cl2, 0.1M OH M(OTf)3, -78 oC M = Al, Bi, In Ph 10% nOe 10% nOe OH H O O O Ph X O Ph Two-Lewis Acid System O 2 OH

R1 R CHO, Na2SO4 Al(OTf)3, -10 oC, 1 h; OH then TiCl4, 45 min R1 O R2 50-70% No problems associated with coexistence of two Lewis acids Yields and Scope of Oxepane Formation O RCHO O O H H H Ph diol

O 55% O O 51% 55% OH OH O O 69% OH OH O O O Ph O 66% O O

Ph O 70% O Ph O 71% OH OH O 62% O Ph O Ph Ph 71% O O'Neil, K. E.; Kingree, S. V.; Minbiole, K. P. C. Org. Lett. 2005, 7, 515-517. Appearance of Trans Oxepane O

O TiCl4 R 0 oC, 45 min O ~1:1 O R O R O PhCHO, Na2SO4 Yb(OTf)3 (1.0 eq); OH R O M OH then TiCl4 (1.1 eq) R Pr Me

iPr Yield 61% 70% 55% R O Inclusion of Sidechain Functionality O RCHO O H H diol NO2 O O OH OH 34% 26% O O

NO2 O O 36% OH OH 30% O O NO2 36% O OH OH O 30% O O NO2 Inclusion of Sidechain Functionality O O OCH3

H H OBn O O O OCH3 O 47% O O 15% Certain chelating groups are tolerated OBn Inclusion of Sidechain Functionality H O O O OBn

H No rearrangement O H O No rearrangement O M R OCH3 O R Productive Chelation N No rearrangement O R O M O R Non-Productive

Chelation Certain chelating groups are tolerated but others fail to rearrange to oxepane Reaction Optimization Alternate Lewis acids Zirconium tetrachloride Alternate drying agents Molecular sieves Alternate solvent systems More or less polar solvents Outline I. Introduction to Cyclopropanes and Heterocycle Formation Strategies II. Proof of Concept: Oxepane Synthesis III. Progress Towards Nitrogenous Heterocycles IV. Radical Strategies V. Future Directions Nitrogen Analogs: Azepines Analogous reaction in nitrogenous heterocycles? R

O NH RCHO, Na2SO4 OH Lewis Acid(s) O N R R N R R Nature of Protecting Group on Nitrogen NH2 PhCHO, Na2SO4 OH Boc NH Lewis Acid(s) PhCHO, Na2SO4 OH Lewis Acid(s)

O O Ph N H LA LA O O N Ph Boc N Ph Boc O Boc = O N H Ph N H

O LA O Ph N H Ph O LA O N Ph Boc N Ph Boc Assembly of Azepine Precursor NH2 O Boc2O; OEt >99% Boc Kulinkovich Cyclopropanation NH O

OEt Ti(O-iPr)4 (1 eq) EtMgBr (4 eq) THF/Et2O (4:1) 72% Boc NH OH Cyclization attempts Boc PhCHO, LA NH No Reaction OH Lewis Acids employed: Al(OTf)3 ZrCl4 Yb(OTf)3 LaCl3 TiCl4 In(OTf)3 BBr3 Bi(OTf)3 Brnsted Acids employed: HCOOH TFA

pTSA O O H H N O Cyclization Attempts with Free Amine PPh3, DIAD, Zn(N3)3-pyr2 OH OH N3 LAH or NaBH4 OH 60% NH2 or PPh3/H2O PhCHO, LA OH O N H Amino alcohol not yet isolated

Ph NH2 OH Outline I. Introduction to Cyclopropanes and Heterocycle Formation Strategies II. Proof of Concept: Oxepane Synthesis III. Progress Towards Nitrogenous Heterocycles IV. Radical Strategies V. Future Directions Radical Cyclization O O M O O M Heterolytic Homolytic Radical Cyclization O

OH [O] O M O O M Heterolytic Homolytic Heterolysis is known for cyclopropanols with mild single electron oxidants (e.g., Mn3+ and Fe3+). Radical Cyclization Utilizing Azide I N3 1. Bu3SnH, AIBN PhH, , 2h n n N Ts

2. TsCl I N3 n = 1, 88% n = 2, 50% Kim, 1994 N N N N N2 n - N2 H N H N Kim, S.; Joe, G. H.; Do, J. Y. J. Am. Chem. Soc. 1994, 116, 5521-5522. Radical Cyclization Towards Heterocycles Mn(pic)3 N3 OH - N2 N3

or FeCl3 O O pic = O N solvent HN O Radical Cyclization Towards Functionalized Heterocycle R N3 R OH Mn(pic)3 R - N2 N3 or FeCl3 O

O pic = O N solvent HN O Progress Towards Piperidine N3 Oxidant OH DMF or benzene N3 HN O O Not observed N3 O X X = H, OH, OOH, Cl

Oxidants Used: FeCl3 Fe(NO3)3 Mn(OAc)3 Mn(pic)3 Recourse for Piperidine Ph Ph N3 Oxidant N3 OH O Ph HN O O Ti(O-iPr)4 (0.1 eq) THF/Et2O (4:1) Ph MgBr O OH

Ph OH Towards the Pyrrolidine O R Tf2O, pyr; OR' OH NaN3, DMF, 24h O R O R Tf2O, NaN3; OR' NH2 Cu(II)SO4 OR' N3 R Kulinkovich Reaction Ti(Oi-Pr)4 (0.1 eq),

EtMgBr, THF/Et2O R OH O [O] R3 N3 R Alper, P. B.; Hung, S.-C.; Wong, C.-H. Tetrahedron Lett. 1996, 6029-6032. R1 N R3 R2 Outline I. Introduction to Cyclopropanes and Heterocycle Formation Strategies II. Proof of Concept: Oxepane Synthesis III. Progress Towards Nitrogenous Heterocycles IV. Radical Strategies V. Future Directions Alternative Ring Size R OH Lewis Acid

RCHO OH R O Lewis Acid O R R O MO H R O R O R Sites of Functionalization on Oxepane Ring O OH Aldehyde, LA OH R O O

R O R OH R OH 4 diastereomers R Aldehyde, LA O O 4 diastereomers O R O R + O O Cyclopropane Functionalization via Cyclopropene M R

N2 Chiral Rh(II) OTIPS R O R O R O O M OTIPS OH OTIPS OH R R R R F

OTIPS OTIPS O R R R O RCHO, LA OH R OH Doyle, M. P.; Protopopova, M.; Mller, P.; Ene, D.; Shapiro, E. A. J. Am. Chem. Soc. 1994, 116, 8492. Mller, P.; Granicher, C. Helv. Chim. Acta 1995, 78, 129. Fox, J. M.; Yan, N. Curr. Org. Chem. 2005, 9, 719. Natural Product Total Synthesis Azepines Piperidines O OH H3C N

H 11 N H OH Spectalinine Coniine H3C O N H O H Stemoamide Oxepanes (7) and Oxocanes (8) Tetrahydropyrans O H3CO Centrolobine OH Cl H

O H Br Isolaurepinnacin O Lauthisan Conclusions Cyclopropanes can be utilized as homo-alkenes to prepare heterocycles A facile two-step procedure has been developed to prepare oxepanes with excellent stereoselectivity Further substitution and alternate heterocycles are being explored Radical cyclization promises another method to deliver heterocycles from cyclopropanols Epilogue on Undergraduate Teaching and Research Quality of Life Opportunities for Funding Satisfaction Direction of research Students The Group

Kerry ONeil, JMU 05 Andrew Blanchard, JMU 07 Seth Kingree, JMU 06 Steve Andrews, JMU 07 Cambria Baylor, JMU 06 Erik Stang, JMU 06 Wheres James Madison University? Funding Acknowledgements NMR: Tom Gallaher and Jeff Molloy Nebraska Center for Mass Spectrometry Drs. Kevin Caran and Scott Lewis James Madison University Future Direction: Cyclopropane Functionalization CO2R CO2R N2 OTIPS TBAF, -78 C Chiral Rh Cat TIPSO

CO2R o TIPSO OTIPS HO OH RCHO, LA O R CHO CO2R R O RR O R RO2C OH Other Backups: Discrete Homoenolate TMS O

O O M O R R R X X R R M X R R R Metals Employed: AgI, AuI, CuII, X R HgII, PdII,

PtII, SnIV Other Backups: Radical HO O O R R R N R N R R R O O HO R R R

O CO2R N O O CO2R CO2R Aza Cope Possibility LA O LA O N R Ph O N R Ph N R Ph Modified Point of Attachment

OH Ti(Oi-Pr)4, PhCH3, rt; then c-C5H9MgCl, THF R O OH H OH H R1 OH R R O R1 Ti (Oi-Pr)n Cha, 2002 OR2 1 R O

OH R3CHO, LA R R R R1 O OLA R1 O R3 R3 H R 15 examples 42-68% yield 3.5-12.2:1 ds O MO RH H Previous

R R1 OR H O RH H Modified Connectivity Precedent For Acyliminium Formation Hsung Precedent R O NHBoc OTBS R = hexyl R OHCO HCO2H THF Toluene R NBoc OTBS NBoc OTBS

61% Hsung, 2004

Recently Viewed Presentations

  • Missing Persons and Amber Alert

    Missing Persons and Amber Alert

    "Line by Line" New Law "A new section of the Law Enforcement Training Act is enacted to read: "Missing Person and Amber Alert Training - a minimum of four hours of combined missing person and AMBER alert training shall be...
  • Sensory Systems The Sensory Structures of the Skin

    Sensory Systems The Sensory Structures of the Skin

    Sensory Systems The Sensory Structures of the Skin ... of the Olfactory Epithelium TEM of the Olfactory Bulb Olfactory Membrane Lamina Propria with Glands of Bowman The Cornea TEM of a Corneal stromal fibroblast (fib) TEM of the Substancia Propria...
  • Data and Metadata Architectures in a Robust Semantic

    Data and Metadata Architectures in a Robust Semantic

    Lets call this ASL (Application Specific language) Tools to manipulate information expressed in language and key data of application (cf coordinate transformations). Lets call this ASTT (Application specific Tools and Transformations) ASL must support Data sources such as sensors (cf...
  • The relationship between income and children&#x27;s outcomes: a ...

    The relationship between income and children's outcomes: a ...

    The relationship between income and children's outcomes: a research synthesis of evidence from Canada. CRDCN National Conference 2012 - Fredericton, NB Oct 23-24 . Annie McEwen (presenting) and Jennifer Stewart. School of Public Policy and Administration. Mention this in an...
  • RefWorks Presentation Fall 2015 - Concordia University

    RefWorks Presentation Fall 2015 - Concordia University

    Concordia University Other titles: Arial Century Schoolbook Wingdings Wingdings 2 Calibri Gill Sans MT Oriel 1_Oriel 2_Oriel 3_Oriel 4_Oriel 5_Oriel 6_Oriel Using Refworks for graduates Learning Objectives Workshop format
  • Social Media - Temple MIS

    Social Media - Temple MIS

    Information systems projects and enterprise architecture. WHAT IS AN ORGANIZATION? To understand the role of IT projects in business,you need to have an idea of what isa (large-scale) organization. ... Marie Martin Company:
  • Beowulf and the Hero&#x27;s Journey:

    Beowulf and the Hero's Journey:

    Most Disney movies follow the hero's journey archetype. Archetype means original pattern. In the arts (literature, film, visual arts, etc.) there are character traits, themes, and plot structures that are repeated.
  • DISSOCIATION THEORY, NEUROPLASTICITY AND THE HEALING OF COMBAT

    DISSOCIATION THEORY, NEUROPLASTICITY AND THE HEALING OF COMBAT

    Non-declarative (implicit) memory - Emotional associations - Procedural memory - Skills and habits - Conditioned sensorimotor responses. Traumatic event/helplessness leads to freeze. Lack of freeze discharge implies lack of completion, events stored in procedural memory, link made between arousal, declarative...