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哥伦比亚教授有机化学课件Pericyclic


A Panoply of Pericyclic Processes
Lecture Notes

Key Reviews: Ene Reaction H. M. R. Hoffmann, Angew. Chem. Int. Ed. Engl. 1969, 8, 556. W. Oppolzer, Angew. Chem. Int. Ed. Engl. 1978, 17, 476. J. M. Conia, Synthesis 1975, 1. [2+2]-Cycloadditions Org. React. 1993, 44, 297. W. Dermuth, Synthesis 1989, 152. Cyclopropanation H. E. Simmons, Org. React. 1973, 20, 1. S. Burke, P. A. Grieco, Org. React. 1979, 26, 361. Pauson-Khand Reaction W. Pauson, Tetrahedron 1978, 41, 5855.

Ene Reactions: Background and Key Principles

H + ene

Y X eneophile

H

Y X
Q ui kTi e?a nd a c m Ph o t o - J PE G d ec om pr es so r ar e ne ed ed t o s ee t h i pi t u r e. s c

O + H Ph O O

O

?
Ene reaction Ph

O O

This reaction is often referred to as the Alder ene reaction, particularly in older (pre-1980s) literature

Kurt Alder (1902-1958)

K. Alder and co-workers, Chem. Ber. 1943, 76, 27.

Ene Reactions: Background and Key Principles

H + ene

Y X eneophile

H

Y X

This reaction is formally classified as a [4+2] cyclization. (Ene = HOMO, Eneophile = LUMO) However, ene reactions typically require much higher temperatures than the DielsAlder reaction to initiate, especially for intermolecular ene reactions as they have a high negative entropy of activation

K. Alder and co-workers, Chem. Ber. 1943, 76, 27.

Ene Reactions: Background and Key Principles

H + ene

Y X eneophile

H

Y X

This reaction is formally classified as a [4+2] cyclization. (Ene = HOMO, Eneophile = LUMO) However, ene reactions typically require much higher temperatures than the DielsAlder reaction to initiate, especially for intermolecular ene reactions as they have a high negative entropy of activation O Typical enophiles R1 Hetero ene reactions R2 R1 R2 R1 N R3 S R2 R3 R1 X Y R4 R2 Z = O, N not S

Z

Z

+ H

X Y

Z

H

K. Alder and co-workers, Chem. Ber. 1943, 76, 27.

Ene Reactions in Total Synthesis: Ene/Retro-Ene Sequence to Protect Indole
O H CO2Me NAc + N H Me Me N N O NMe 150 ° C, 1 min N Me Me CH2Cl2, 0° C, 1 min MeN O N NH H CO2Me NAc N H O N N NMe O

O MTAD

MTAD = N-methyltriazolinedione

P. S. Baran, C. A. Guerrero, E. J. Corey, J. Am. Chem. Soc. 2003, 125, 5628. P. S. Baran, C. A. Guerrero, E. J. Corey, Org. Lett. 2003, 5, 1999.

Ene Reactions in Total Synthesis: Ene/Retro-Ene Sequence to Protect Indole
O H CO2Me NAc + N H Me Me N N O NMe 150 ° C, 1 min N Me Me CH2Cl2, 0° C, 1 min MeN O N NH H CO2Me NAc N H O N N NMe O

O MTAD

MTAD = N-methyltriazolinedione

Me Me O H

N H N N

MTAD, CH2Cl2, 0 ° 1 h; C, H O
2 (O2, 1O

N Me O Me H O MeN NH H N O N N N

OH H O 110 ° C, 30 min (70% overall based on r.s.m.) Retro Ene reaction

N Me Me H O H

OH N N H O

N H Me Me

methylene blue) Ene reaction

Me Me

N H Me Me okaramine N

P. S. Baran, C. A. Guerrero, E. J. Corey, J. Am. Chem. Soc. 2003, 125, 5628. P. S. Baran, C. A. Guerrero, E. J. Corey, Org. Lett. 2003, 5, 1999.

Ene Reactions in Total Synthesis: Double Ene Sequence
O Ph HN H + N H O CH3CN, 25 ° C Me Aza-ene reaction Ph HN N O O Me Imineenamine tautomerization O Ph HN NH O Me

Intramolecular (56-75%) cyclization

O Ph HN N Me OH

J.-H. Zhang and co-workers, Tetrahedron Lett. 1998, 39, 9237.

Ene Reactions in Total Synthesis: Double Ene Sequence
O Ph HN H + N H O CH3CN, 25 ° C Me Aza-ene reaction Ph HN N O O Me Imineenamine tautomerization O Ph HN NH O Me

Intramolecular (56-75%) cyclization

Ar -[ArCOOH] Me HO N N Me OH (70%) Me HO N

O O N Me OH Me Ph

O

imidazo[1,2,3-ij][1,8] naphthyridine

CH3CN, H2O, 25 ° C [repetition of sequence above]

HN

N

Me OH

J.-H. Zhang and co-workers, Tetrahedron Lett. 1998, 39, 9237.

Ene Reactions in Total Synthesis: Tandem Oxy-Cope/Carbonyl Ene Sequence
H Me OH Me Me HO OTBDPS Me DBU, toluene 220 ° C Oxy-Cope OTBDPS rearrangement Me OH Me O Me H H H H

Enol-Keto tautoOTBDPS merization

OTBDPS

TBDPS = t-butyldiphenylsilyl

TBDPSO H Me

H H H

O

L. Barriault, D. H. Deon, Org. Lett. 2001, 3, 1925.

Ene Reactions in Total Synthesis: Tandem Oxy-Cope/Carbonyl Ene Sequence
H Me OH Me Me HO OTBDPS Me DBU, toluene 220 ° C Oxy-Cope OTBDPS rearrangement Me OH Me O Me H H H H

Enol-Keto tautoOTBDPS merization

OTBDPS

TBDPS = t-butyldiphenylsilyl

H Me O HO HO

Me

H

H

OTBDPS Transannular ene reaction (63%) H H H

TBDPSO H Me

Me

HO OTBDPS

OH Me

Me O arteannuin M

O

L. Barriault, D. H. Deon, Org. Lett. 2001, 3, 1925.

Ene Reactions in Total Synthesis: A Carbonyl Ene Reaction (Oxidative Prins Cyclization)

PCC, CH2Cl2 OH H H O

Carbonyl ene reaction OH

H

PCC, (67%) CH2Cl2 Acid-catalyzed reactions of aldehydes with alkenes are known collectively as Prins reactions. When they are conducted in the absence of water, a carbonyl ene reaction takes place. isocycloseychellene

O

S. C. Welch and co-workers, J. Org. Chem. 1985, 50, 2668.

Oxy-Ene Reactions: Also Known as Conia Reactions
Me O 350-370 ° C 30 min Me OH Conia reaction Me O Me O Me

Me Epimerized to the more stable trans isomer

J. M. Conia and co-workers, Bull. Chim. Soc. Fr. 1969, 818. J. M. Conia and co-workers, Tetrahedron Lett. 1974, 2931.

Oxy-Ene Reactions: Also Known as Conia Reactions
Me O 350-370 ° C 30 min Me OH Conia reaction Me O Me O Me

Me Epimerized to the more stable trans isomer Me Me O Conia reaction Me

Me

Me O 350-370 ° C 30 min

Me

Me OH

J. M. Conia and co-workers, Bull. Chim. Soc. Fr. 1969, 818. J. M. Conia and co-workers, Tetrahedron Lett. 1974, 2931.

Oxy-Ene Reactions: Also Known as Conia Reactions
Me O 350-370 ° C 30 min Me OH Conia reaction Me O Me O Me

Me Epimerized to the more stable trans isomer Me Me O Conia reaction Me

Me

Me O 350-370 ° C 30 min

Me

Me OH

Me O 335 ° C 60 h Conia reaction

Me O (50%) Conia reaction

Me

O

Me

H

J. M. Conia and co-workers, Bull. Chim. Soc. Fr. 1969, 818. J. M. Conia and co-workers, Tetrahedron Lett. 1974, 2931.

Oxy-Ene Reactions: Metal-Catalyzed Conia-Type Reactions
O O O O R1 O OR2 O PAr2 Pd(OTf)2 PAr2 (10 mol %) R1

O

O OR2

Yb(OTf)3 (20 mol %) Conia reaction

HO Me O Me laurebiphenyl

B. K. Corkey, F. D. Toste, J. Am. Chem. Soc. 2005, 127, 17168.

Ene Reactions in Total Synthesis: Asymmetric, Metal-Promoted Ene Reaction

Me Me O H EtO2C H N H N EtO2C O N R R = COPh Me HO2C HO2C N H kainic acid Me O

Ph MgClO4, Ph Me CH2Cl2, 25 ° 3 h C, (72%) O N (65% e.e.) R Metal-promoted R = COPh ene reaction

First of 53 total syntheses of this compound that can produce gram quantities readily; only 6 steps and 20% yield overall

Q. Xia, B. Ganem, Org. Lett. 2001, 3, 485.

Ene Reactions in Total Synthesis: Selenium Dioxide Oxidation Reactions
SeO2, t-BuOOH (38%)

CO2Me

HO

CO2Me

O O mokupalide

H Se O O

Ene reaction

O Se OH

[2,3]-sigmatropic rearrangement

O Se OH

OH Nu

F. W. Sum, L. Weiler, J. Am. Chem. Soc. 1979, 101, 4401. K. B. Sharpless and co-workers, J. Am. Chem. Soc. 1973, 95, 7917.

Photochemical [2+2] Reactions in Total Synthesis: Intramolecular Examples
OEt Me O Me 1. LDA, MeI 2. MgBr OEt Me Me HCl work-up (74% overall) Me O Me Me

OH Me

[2+2] h? cycloaddition (77%)

O Me Me Me Ph3P CH2 DMSO, 70 ° C (77%)

Me Me

Me

M. C. Pirrung, J. Am. Chem. Soc. 1979, 101, 7130. M. C. Pirrung, J. Am. Chem. Soc. 1981, 103, 82.

Photochemical [2+2] Reactions in Total Synthesis: Intramolecular Examples
OEt Me O Me 1. LDA, MeI 2. MgBr OEt Me Me HCl work-up (74% overall) Me O Me Me

OH Me

[2+2] h? cycloaddition (77%)

Me Me

O p-TsOH, benzene, ? (98%) Can you rationalize a mechanism? Me Me Me Ph3P CH2 DMSO, 70 ° C (77%)

Me Me

Me Me isocomene

Me

M. C. Pirrung, J. Am. Chem. Soc. 1979, 101, 7130. M. C. Pirrung, J. Am. Chem. Soc. 1981, 103, 82.

Photochemical [2+2] Reactions in Total Synthesis: Intramolecular Examples
O Me sunlight Me carvone 1 year

Me Me O carvonecamphor

HO H O

h?

H H

H H O O

Incredibly strained systems can be fashioned by [2+2] cycloadditions!

Photochemical [2+2] Reactions in Total Synthesis: Intramolecular Examples
O O Br H H h? [2+2] cycloaddition O Br Br 50% aq. KOH (50% overall)

O

Br

P. E. Eaton, T. W. Cole, J. Am. Chem. Soc. 1964, 86, 962. P. E. Eaton, T. W. Cole, J. Am. Chem. Soc. 1964, 86, 3157.

Photochemical [2+2] Reactions in Total Synthesis: Intramolecular Examples
O O Br H H h? [2+2] cycloaddition O Br Br 50% aq. KOH (50% overall) O Br O Br

O

Br O O

Note: The Favorskii rearrangement is an excellent way to achieve ring contraction on symmetrical substrates; on non-symmetrical compounds, two products will often result unless there is a distinct bond breaking preference.

CO2H HO2C cubane

Favorskii rearrangement (30%)

O O HO OH

P. E. Eaton, T. W. Cole, J. Am. Chem. Soc. 1964, 86, 962. P. E. Eaton, T. W. Cole, J. Am. Chem. Soc. 1964, 86, 3157.

Photochemical [2+2] Reactions in Total Synthesis: Intramolecular Examples
O Me Me Me CuI, THF Me O Me Me H2CO Tandem vicinal functionalization Me O OH Me Me

MgBr

1. TsCl 2. DBU Me Me Olefination (reaction to be unveiled later) Me Me Me h? (67%) [2+2] cycloaddition Me

O

O

Me Me

Me panasinene

C. R. Johnson and co-workers, J. Am. Chem. Soc. 1981, 103, 7667.

Photochemical [2+2] Reactions in Total Synthesis: Intramolecular Examples
EtO O LDA

EtO

O LiAlH4

O

Me

Me

I

Me

Me

Me

Me

[2+2] cycloaddition O O O

h?

O O

O O3 H Me

O

Me H Me Me hibiscone C

Me

Me

H Me

A. B. Smith and co-workers, J. Am. Chem. Soc. 1982, 104, 5568.

Photochemical [2+2] Reactions in Total Synthesis: Intramolecular Examples
TBDPSO O L-Proline O Me TBDPSO H thermodynamic O product Me H OH OH OBn O O O H O Me H littoralisone H O OH O 1. h? 2. H2, Pd/C [2+2] OH cycloaddition (84%) OH O O H O Me H O OBn OBn O OBn O H DMSO O
N O OH

Me H

H OTBDPS (91%)

TBDPSO

H O

Me H OH kinetic product

Me H OAc

I. K. Mangion, D. W. C. MacMillan, J. Am. Chem. Soc. 2005, 127, 3696.

Photochemical [2+2] Reactions: Intermolecular Examples and Regiochemistry
Intermolecular reactions typically lack regioselectivity . . . h?

+

Et Me

and Et

Me

E. J. Corey and co-workers, J. Am. Chem. Soc. 1964, 86, 5570.

Photochemical [2+2] Reactions: Intermolecular Examples and Regiochemistry
Intermolecular reactions typically lack regioselectivity . . . h?

+

Et Me

and Et

Me

unless strongly electron-withdrawing and/or donating substituents are involved O + CO2Me h? H O MeO + OMe h? O H OMe OMe O Excited state reaction O O Ground state reaction

H

CO2Me

H

E. J. Corey and co-workers, J. Am. Chem. Soc. 1964, 86, 5570.

Photochemical [2+2] Reactions in Total Synthesis: An Inter-/Intramolecular Cascade
O MeO2C + h? [2+2] cycloaddition O

H CO2Me Ph3P=CH2 Me H Wittig reaction

H CO2Me

Me H

P. A. Wender and co-workers, Tetrahedron Lett. 1982, 23, 1871.

Photochemical [2+2] Reactions in Total Synthesis: An Inter-/Intramolecular Cascade
O MeO2C + h? [2+2] cycloaddition O

H CO2Me Ph3P=CH2 Me H Wittig reaction

H CO2Me

Me H

Retro [2+2] 210 ° C, cycloaddition 2 h

CO2Me

P. A. Wender and co-workers, Tetrahedron Lett. 1982, 23, 1871.

Photochemical [2+2] Reactions in Total Synthesis: An Inter-/Intramolecular Cascade
O MeO2C + h? [2+2] cycloaddition O

H CO2Me Ph3P=CH2 Me H Wittig reaction

H CO2Me

Me H

Retro [2+2] 210 ° C, cycloaddition 2 h

OHC Me OH CHO H Me Me warburganal

Me

CO2Me

Ene reaction

H CO2Me

H

P. A. Wender and co-workers, Tetrahedron Lett. 1982, 23, 1871.

Photochemical [2+2] Reactions in Total Synthesis: Intermolecular Examples
CBz CBz + CBz O

N BzC N

Zn, AcOH (80%)

N BzC N

O h? MeCN (40%) [2+2]

N BzC N

Br Br

CO2H

??Hf = +19.6 kcal/mol

pentacycloanemmoxic acid

V. Mascitti, E. J. Corey, J. Am. Chem. Soc. 2004, 126, 15664.

Photochemical [2+2] Reactions in Total Synthesis: Tethered Intramolecular Example for Ladderane Synthesis
N HO OMe

OH

N

N

HO

MeO

OH

N

Structure organized by a series of hydrogen bonds

h? in solid state (100%)

[2+2] cycloaddition cascade sequence Pyr Pyr

Pyr Pyr X. Gao, T. Friscic, L. R. MacGillivray, Angew. Chem. Int. Ed. 2004, 43, 232.

Photochemical [2+2] Reactions: The Paterno-Buchi Reaction
Paterno (1909) Me + Me Buchi (1954) Me + Me Me n-Pr O h? Me O Me Me n-Pr oxetane ring system Me Ph O Me sunlight Me Me O Ph + O Me Me Me Ph

E. Paterno, Gazz. Chim. Ital. 1909, 39, 237. G. Buchi and co-workers, J. Am. Chem. Soc. 1954, 76, 4327.

Photochemical [2+2] Reactions: The Paterno-Buchi Reaction
Paterno (1909) Me + Me Buchi (1954) Me + Me Me n-Pr O h? Me O Me Me n-Pr oxetane ring system Me Ph O Me sunlight Me Me O Ph + O Me Me Me Ph

General features: -carbonyl can be either an aldehyde or ketone; alkene should be electron-rich -carbonyl substrate is energy absorbing -often highly regioselective due to radical-based mechanism for coupling Me O Me Me n-Pr Me Me Me O n-Pr

E. Paterno, Gazz. Chim. Ital. 1909, 39, 237. G. Buchi and co-workers, J. Am. Chem. Soc. 1954, 76, 4327.

Photochemical [2+2] Reactions: The Paterno-Buchi Reaction in Action
Me Me Me O Me What pericyclic reaction was used to generate the starting material for this sequence? Li+ LDBB O Me Me H Me oxosilphipefol-6-ene Me LDBB, THF, -78 to -10 ° C, 35 h h? (79%) Me Me Me O Me Me Me Me O H Me

PCC, DMF (84%)

HO Me Me Me H Me (57%) Me

O Me

Me

H Me

T. J. Reddy, V. H. Rawal, Org. Lett. 2000, 2, 2711.

Photochemical [2+2] Reactions: The Paterno-Buchi Reaction in Action
H + N CO2Me C9H19 h? (53%) [2+2] O C9H19 N CO2Me note the stereochemistry of this addition H Ph

O Ph

H2, Pd(OH)2/C (81%)

HO C9H19 N CO2Me

Ph

LiAlH4, (91%) THF, ? HO C9H19 OH

HO C9H19 N Ph Me preussin

HO C9H19

N Ph

N Ph

T. Bach, H. Brummerhop, Angew. Chem. Int. Ed. 1999, 37, 3400.

Photochemical [2+2] Reactions: The Paterno-Buchi Reaction in Action
OH CO2Et O

EtO2C + O

H O

h? (65%) [2+2]

H

CO2Et O

EtSH, BF3?OEt2

H

H Why this ring closure regiochemistry?

O

(70%)

O

H

H O

H OAc

H

OH CO2Et

H euplotin A

O

O

SEt

R. A. Aungst, R. L. Funk, J. Am. Chem. Soc. 2001, 123, 9455.

Photochemical [2+2] Reactions: The Paterno-Buchi Reaction in Action

C8H17 + O O

H

H h? (100%) [2+2] cycloaddition O H

C8H17 O

H2, Rh/Al2O3 (97%)

H

C8H17 O

O

H

0.1 N HCl (96%) in THF

Note: These photocycloadditions are all racemic events; rendering them asymmetric remains an unexplored frontier for synthetic methods development

H O O

C8H17 O OH

H

C8H17 OH O

H O avenaciolide

[putative aldol product]

S. L. Schreiber, A. H. Hoveyda, J. Am. Chem. Soc. 1984, 106, 7200. For more on furans, see: Classics in Total Synthesis I, Chapter 20.

The Simmons-Smith Cyclopropanation: A [2+2] Pericyclic Reaction
Et2Zn + R5CHI2 -[EtI]

EtZnCH2I R2 R1 R3 R4 EtZn I CH2 R3 R4

R5 = H, Me, Ph Formally the addition of a carbene to an olefin

R2 R1

CH2

R3 R4

-[EtZnI]

R2 R1

butterfly mechanism

For a review, see: H. E. Simmons, Org. React. 1973, 20, 1.

The Simmons-Smith Cyclopropanation: A [2+2] Pericyclic Reaction
Et2Zn + R5CHI2 -[EtI]

EtZnCH2I R2 R1 R3 R4 EtZn I CH2 R3 R4

R5 = H, Me, Ph Formally the addition of a carbene to an olefin

R2 R1

CH2

R3 R4

-[EtZnI]

R2 R1

butterfly mechanism Stereochemistry of starting alkene is preserved in the product If a fragment installs a group other than H on the new cyclopropane ring system (i.e. R5 = Me, Ph), it prefers to be syn to the substituents on the alkene For a review, see: H. E. Simmons, Org. React. 1973, 20, 1.

The Simmons-Smith Cyclopropanation: Examples in Natural Product Total Synthesis

Me Me O Me O Me

Zn-Cu, CH2I2, Et2O, 35 ° 6 h C, (60%) Double-directed Simmons-Smith Cyclopropanation Me H

Me Me O O Me H H H

3 steps Me S MeO H N H curacin A Me H O HO H Me H

S. Iwasaki and co-workers, Tetrahedron Lett. 1996, 37, 4397.

The Simmons-Smith Cyclopropanation: Examples in Natural Product Total Synthesis

Me Me O Me O Me

Zn-Cu, CH2I2, Et2O, 35 ° 6 h C, (60%) Double-directed Simmons-Smith Cyclopropanation Me H

Me Me O O Me H H H

Can you guess the transformations? Me S MeO H N H curacin A Me H

3 steps

O HO H Me H

S. Iwasaki and co-workers, Tetrahedron Lett. 1996, 37, 4397.

The Simmons-Smith Cyclopropanation: Examples in Natural Product Total Synthesis

O H O TBDPSO

Me

CH2I2, Et2Zn benzene (92%) Simmons-Smith TBDPSO cyclopropanation

H O H O H

H Me

H O Me made from a Claisen rearrangement

H

H O Me

O O

H

H Me

H OAc Me acetoxycrenulide

L. A. Paquette and co-workers, J. Am. Chem. Soc. 1995, 117, 1455.

The Simmons-Smith Cyclopropanation: Examples in Natural Product Total Synthesis

Me

O O MeCN, ? (66%) Intramolecular Diels-Alder reaction

Me

O O

Me

H Me SimmonsSmith cyclopropanation (92%) O O

CH2I2 (16 equiv), Et2Zn (8 equiv), toluene, 25 ° 6 h C, Me H Me Me trans-dihydroconfertifolin O O

Me H2, PtO2 AcOH (99%)

H Me

D. F. Taber and co-workers, J. Org. Chem. 2002, 67, 4501.

The Simmons-Smith Cyclopropanation: Examples in Natural Product Total Synthesis
O O OH
O Me Me Me Me

Me2N CH3CHI2, Et2Zn, CH2Cl2/DME, -10 ° C Asymmetric Simmons-Smith cyclopropanation OH
O Me Me Me

NMe2 O B Bu O (1.2 equiv)

(86%)

Best method for asymmetric cyclopropanation; requires stoichiometric ligand and works for allylic alcohols only

Me

Me

OH OH O CO2H O Me Me Me (+)-ambruticin Me Me

P. Liu, E. N. Jacobsen, J. Am. Chem. Soc. 2001, 123, 10772. Cyclopropanation method: A. B. Charette, H. Juteau, J. Am. Chem. Soc. 1994, 116, 2651.

Other Cyclopropanation Methods: The Reactions of Carbenes

+

CH2

CH2 > CHCl > CCl2 > CBr2 > CF2

For a review, see: W. Kirmse, Carbene Chemistry 1971, 313.

Other Cyclopropanation Methods: The Reactions of Carbenes

+

CH2

CH2 > CHCl > CCl2 > CBr2 > CF2

OMe

KOtBu, CHCl3 [:CCl2]

Cl

Cl OMe

MeLi, CH2Cl2 N H [:CHCl] N H

H Cl

For a review, see: W. Kirmse, Carbene Chemistry 1971, 313.

Other Cyclopropanation Methods: The Reactions of Carbenes

+

CH2

CH2 > CHCl > CCl2 > CBr2 > CF2

OMe

KOtBu, CHCl3 [:CCl2]

Cl

Cl OMe

Cl O

MeLi, CH2Cl2 N H [:CHCl] N H

H Cl N

For a review, see: W. Kirmse, Carbene Chemistry 1971, 313.

Other Cyclopropanation Methods: The Reactions of Carbenes
O Cl Me Me Me CH2N2 O N2 Me Me Cu, ? Me O

Carbene-based cyclopronation O Me Me

For a review, see: S. Burke, P. A. Grieco, Org. React. 1979, 26, 361.

Other Cyclopropanation Methods: The Reactions of Carbenes
O Cl Me Me Me CH2N2 O N2 Me Me Cu, ? Me O

Carbene-based cyclopronation OLi Li/NH3 Regioselective Me enolate formation Me O Me Me

For a review, see: S. Burke, P. A. Grieco, Org. React. 1979, 26, 361.

Other Cyclopropanation Methods: The Reactions of Carbenes
O Cl Me Me Me CH2N2 O N2 Me Me Cu, ? Me O

Carbene-based cyclopronation OLi Li/NH3 Regioselective enolate formation O Me Me HCO2H H2O Me OH Me O

For a review, see: S. Burke, P. A. Grieco, Org. React. 1979, 26, 361.

Other Cyclopropanation Methods: The Reactions of Carbenes
O O Cu, ? O O O Me O

Me

Me

Me

Carbene-based cyclopronation

Me

Me O

N2 O O 1. NaH, CO(OMe)2 2. NaBH4 O O

H Me Me OH

MeO2C

P. Deslongshamps and co-workers, Can. J. Chem. 1980, 58, 2460.

Other Cyclopropanation Methods: The Reactions of Carbenes
O O Cu, ? O O O Me O

Me

Me

Me

Carbene-based cyclopronation

Me

Me O

N2 O O 1. NaH, CO(OMe)2 2. NaBH4 O HCl, THF Me Me HO Me agarospirol MeO2C Me Me O

O Me Me

O

H Me OH

MeO2C

P. Deslongshamps and co-workers, Can. J. Chem. 1980, 58, 2460.

Other Cyclopropanation Methods: The Reactions of Carbenes
O CO2Et TsN3 Diazo transfer C5H11 O CO2Et N2 C5H11 Cu, ? toluene Carbene-based cyclopronation

O CO2Et H C5H11

Homoconjugate PhSH, addition KOtBu

O CO2H C5H11 H OH prostaglandin A2 sulfoxide [2,3]-sigmatropic rearrangement employed in these steps

O CO2Et C5H11 H SPh

D. F. Taber and co-workers, J. Am. Chem. Soc. 1977, 99, 3513.

The Pauson-Khand Reaction: A [2+2+1] Cycloaddition
transition metal complex (1 equiv), solvent, heat or transition metal complex (<1 equiv), promoter, solvent, CO atmosphere O R1 R2 R6 R5

R5 R1 R2 + R3 terminal or internal alkyne

R6 R4

R R3 4 cyclopentenone

For a review, see: P. Schore, Chem. Rev. 1988, 88, 1081.

The Pauson-Khand Reaction: A [2+2+1] Cycloaddition
transition metal complex (1 equiv), solvent, heat or transition metal complex (<1 equiv), promoter, solvent, CO atmosphere O R1 R2 R6 R5

R5 R1 R2 + R3 terminal or internal alkyne

R6 R4

R R3 4 cyclopentenone

>

>

>> does not react

For a review, see: P. Schore, Chem. Rev. 1988, 88, 1081.

The Pauson-Khand Reaction: A [2+2+1] Cycloaddition
transition metal complex (1 equiv), solvent, heat or transition metal complex (<1 equiv), promoter, solvent, CO atmosphere O R1 R2 R6 R5

R5 R1 R2 + R3 terminal or internal alkyne

R6 R4

R R3 4 cyclopentenone

>

>

>> does not react

metal complexes: Co2(CO)8, Fe(CO5), Ru2(CO)12, Ni(COD)2, W(CO)6, Mo(Co)6 promoter: NMO, TMANO, RSCH3, h?, "hard" Lewis bases Regioselectivity: Larger alkyne substituent ends up next to the ketone of the product; alkene selectivity is low in intermolecular reactions, high in intramolecular events. For a review, see: P. Schore, Chem. Rev. 1988, 88, 1081.

The Pauson-Khand Reaction: Examples in Complex Molecule Synthesis
Me O H Me H Me carene H Me H Me O Me Co2(CO)8, pet. ether 25 ° C (100%) (CO)6Co2 H Me H Me O O Me

H2C=CH2 (25 atm), TMANO, toluene, 40 ° 24 h C, (81%)

PausonKhand Reaction

Me O ?2H2O N Me Me TMANO

O H H Me Me taylorione Me O H Me H Me

O

O Me

J. G. Donkervoort and co-workers, Tetrahedron 1996, 52, 7391.

The Pauson-Khand Reaction: Examples in Complex Molecule Synthesis
Co2(CO)8, benzene (87%) Me Me OTBDPS Co2(CO)6 Me Co2(CO)6 OTBDPS

OTBDPS

TMANO (6 equiv), PausonCH2Cl2, -78 ° to 25 ° Khand C C (85%) Reaction HO Me H H H O MeO2C H O TBSO MeH

H Me OH

Me O

Me

HO

OH Me HO Me HO kalmanol

H

H

H OTBDPS

L. A. Paquette and co-workers, J. Org. Chem. 1995, 60, 6912.

The Pauson-Khand Reaction: Examples in Complex Molecule Synthesis
Me H O H TMS NMO, CH2Cl2, 25 ° 12 h C, (70%) PausonKhand Reaction O Me H Me H O H H epoxydictymene H Me Me H H Me H O H Me Me OEt Me Me 1. Co2(CO)8 2. EtAlCl, CH2Cl2 (83%) Nicholas reaction Me H Co(CO)3 Co(CO)3 Me Me H H O

S. L. Schreiber and co-workers, J. Am. Chem. Soc. 1997, 119, 4353.

The Pauson-Khand Reaction: Examples in Complex Molecule Synthesis
Me OTBS Co2(CO)8, benzene (92%) THPO (CO)6Co2 THPO Co2(CO)6 NMO?H2O, CH2Cl2, THF (89%, 94% d.s.) Me OH H PausonKhand Reaction Me OTBS H THPO O Me OTBS OTHP Me OTBS

Highly diastereoselective reaction; OTBS group occupies a pseudoequatorial position based on its bulk

N

O

13-deoxyserratine

S. Z. Zard and co-workers, Angew. Chem. Int. Ed. 2002, 41, 1783.


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