Jimin Kim

The Sorensen Group, Department of Chemistry

Jimin Kim

The Sorensen Group, Department of Chemistry

August 23, 2006

Allenes as Products, Substrates, or Intermediatesin

Organometallic Transformations

Structure of Allene

Allenes: 1,2-dienyl compounds with stereogenic axis

In 1875, Van’t Hoff had expected an allene structure

In 1887, Burton and von Pechmann reported the first documented synthesis

CH3

HH

H3C H3C

H H

CH3

Chirality of Allene

(M)-2,3-pentadiene (P)-2,3-pentadieneStereogenic Axis

H

CH3

Counter-clockwise

M

Clockwise

P

H

CH3

HH3CHH3C

Natural Allenes

Representative natural products containing an allene moiety

Hoffmann-Roder, A.; Krause, N. Angew. Chem. Int. Ed. 2004, 43, 1196.

nC8H17

H

H Megatomoic Methyl Ester

Me Me

O

O

O

O OH

OHHO

HO

OHH Me

OH

HMe

OHO

Cinnamoside

O

O

HH

Br

HH

H

BrCl

H

NH2H

O

OHO

O

Me

AcO

H

H

H

AcO

HH

Ginamallene

Obtusallene

4,5-Dienoic aminoacid

HO

OH

H

H

H

BrHBr

H

Kumausallene

HNHO

Isodihydrohistrionicotoxin

Me Me

AcOMe

OH

H

Me

Me OO

Me OH

Me Me

O

Peridininisolation 1890; structure 1971; synthesis 2002

CO2Me

Preparation Methods

X

H

Isomerization Reactions

Xbase

Mostly

X = O, N, P, S, R-CO, C=C, Si, Sn

E (Kcal/mol) +2.1 +20.2

R

HO H

CH2O, iPr2NH

CuBr, dioxane

Crabbe Homologative Allenylation

R

HO H

H

Simple trial with many functional groupstolerance

R'

O H

O

R

i. LDA ii. TMSCl

iii. 67oC iv. CH2N2

R'

H

R

CO2Me

Claisen Protocol

Sigmatropic Rearrangements

A variety of[2,3]-Wittig, [2,3]-Sigmatropics are well established

MsO H

R2CuLiH

R

H

Metal Mediated SN2' Type Substitutions

Various nucleophiles and metals have been utilizedfor this transformation

π-Facial Aspects of SN2’

Self-immolative chirality trasfer from center to axis chirality

XR2R1H

XR2R1H

Nu

anti-modeNu

syn-modeBoth modes are stereoelectronically allowed

R1H Nu

H R1H H

Nu

π∗

σ∗

X

H

N, O, S nucleophile

cuprate, Pd, Ni...d-block elements

Syn-substitution

Nu

Anti-substitution

Nu

SN2'

In general,

Syn SN2’ Displacement

O

H

N H

N H

COPhCl2

NO

COPhCl2H Syn

anti N

O

H

COPhCl2

diaxial..π−πwell overlap!

H

can't interact

N

N

Chair

Twist

"Stereoelectronic Effects in Organic Chemistry"Deslongchamps, P. Pergamon, 1983, pp.174-178.

Mechanistic Aspects of Syn SN2' Reaction

O

OPhCl2

NH

O

OPhCl2 N

HN NSyn Syn

Stork, G. et al., J. Am. Chem. Soc. 1953, 75, 4119; 1977, 99, 3850

Anti SN2’ Displacement

Combine

Mechanistic Behavior of anti-SN2' substitution of Proparylic X

Organocuprate and Organocopper Compounds

X

anti

RCu-L CuIIIRL

RCu-LCu

R L

CuRanti-SN2' displacement of allylicX syn-addition to triple bond

−CuL

−X

syn

R

XH

R1RCuX MgX Cu

XHR1

R X Cu

XHR1

RX

H H−X

CuIII

HHR1

RX −CuX

reductiveelimination

R

HHR1

Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1984, 25, 3063.Elsevior, C. J.; Vermer, P. J. Org. Chem. 1989, 54, 3726.Krause, N. Ed., "Mordern Organocopper Chemistry" Wiley-VCH, 2002.

MgX

Anti vs Syn Selectivity

OMe

BuH BuMgX CuBr (5 mol%)

P(OEt)3Et2O

X = I

X = Cl

Bu

H Bu

H anti : syn = 98 : 2

anti : syn = 20 : 80Bu

H H

Bu

BuMgX

CuBr (5 mol%)PBu3, Et2O

X = Br

X = Cl

anti : syn = 100 : 0

anti : syn =12 : 88

O

CuBr (5 mol%)Me3SiCl, Et2O

OH

Bu

H

OH

H

Bu

(without TMSCl, 35 : 65)

Alexakis, A. et al. J. Am. Chem. Soc. 1990, 112, 8042; Tetrahedron 1991, 47, 1677.

Plausible Pathways

OMe

Bu BuCuBr MgXBu

H

Cu

MeOBuH

Br MgXanti-elimination Bu

H Bu

H

X = I favorBuMgX + CuBr

δ+δ−

+ MeOMgXether

δ+δ−

ether

Hδ+δ−

ether

Bu

H H

Bu

MgX2 X = Cl favor

Bu

H

Mg

O

HBu

- CuBr

Cl

Me

MgCl

Cl

syn-elimination+ MeOMgX

R2Mg + MgX2 2 RMgXK

K = I > Br > ClTHF >> ether

1) Schlenk Favor?

2) Only for Cl?

O

OMgCl

H

Bu

O

Cu BuXMg BrBuCuBr MgX

OMgX

Bu

HX = Br favor

X = Cl favor

MgCl2O

H

MgCl

MgCl

Clanti

syn

OSiMe3

H

BuMe3SiClincrease MgCl2

enhance syn selectivity

Bu

SN2’: C-C Bond Formation

OTBS

THPO OPhOTHP

OHH

1) CBr4, PPh3

2) CuCO2Me

OTBS

THPO OPhOTHP

H

H

CO2Me

HO OPhOH

H

H

CO2H

O

Enprostil

Cooper, G. F. et al. J. Org. Chem. 1993, 58, 4280.

N

S

O

O H

OAcPh2CHO2C

1) MgBr

2) Tf2O, pyr N

S

O

H

OAcPh2CHO2C

TfO2 tBuLi, CuCN

N

S

O

H

OAcPh2CHO2C

HtBu

Buyanak, J. D. et al. J. Am. Chem. Soc. 1994, 116, 10955.

SN2’: C-X Bond Formation

Crimmins, M. T.; Emmitte, K. A.. J. Am. Chem. Soc. 2001, 123, 1533.

O

O

H

HEt

TESO

HOH 1) Sharpless

2) PPh3, NCS

O

O

H

HEt

TESO

HCl 1) LDA

2) ArSO2ClO

O

O

H

HEt

TESO

H

OSO2Ar

LiCuBr2 67%

O

O

H

HEt

TESO

HBr

H1) PPTS, MeOH

2) CBr4, Oct3P

O

O

H

HEt

HBr

H

HHBr

PhMe

OTs

OMeLiCuBr2

75%Ph

OMe

H

Me

BrMeCu(CN)Li

PhMe

Me

OMe

MeO2CSnMe3

Me

NHBoc

1) Cp2ZrHCl, then I2

2) PdCl2(MeCN)2

3) LiOH, then H3O+

HO2C

Me

NHBocPh

Me Me

OMe

N-Boc-ADDA

(-)-Isolaurallene

D'Aniello, F. Mann, A.; Taddei, M. J. Org. Chem. 1996, 61, 4870.

SN2’: C-H Bond Formation

Maumeler, A. et al. Hel. Chim. Acta 1990, 73, 700.

Et3SiO MeO

Me

OHMe Me

Dibal-HEt3SiO Me

O

Me

OAlMe Me

AlH

iBuiBu

Syn

Et3SiO MeOH

Me MeH

Me

OH

1) MnO22) H3O+

HO MeOH

Me MeH

Me

O

Grasshopper ketone

OH

THPO

HR

LiAlH4

Al O

HTHPO

HR

HH Li

Anti

HR

OH

HBerger, A. et al. Synthesis 1989, 93.

R1

H

R2

OHNBSH

Ph3P,DEADR1

R2

HNNH

HSO2Ar

HR1

R2

H

Syn

Myers, A.; Zheng, B. J. Am. Chem. Soc. 1996, 118, 4492.; Kitching, W. J. Org. Chem. 2003, 68, 3739.

-NO2PhSO2HR1

R2

HNNH - N2

Pd Catalyzed Reactions

R1X

R2H

Pd(O)R1

PdIIX

L LR2

H Ph

ZnCl2, iPr2NH

CuI

Anti

R1

R2

H

Ph 85% ee from 93% ee

Chem. Commun. 1997, 2083.

X = OCO2Me, Pd(PPh3)4

CO (200 psi)rt, MeOH/THF X = OMs, Pd2(dba)3, PPh3

R1

R2

H

MeOO 70% ee from 80% ee

LiEt3BH X = OMs, Pd(PPh3)4

R1

H R2

H

49% ee from 58% ee

Tetrahedron Lett. 1984, 25, 845.

J. Org. Chem. 1997, 62, 367.

Pd Catalyzed Allylic Substitution

nC8H17Br

Pd(dba)2 (10 mol%)

H2C(CO2Me)2, CsOtBu(R)-segphos

nC8H17

PdP P

*

77% ee

nC8H17

HCO2Me

CO2MeH

O

O

O

O

PPh2PPh2

1) KOH, then H3O+, 100 oC 2) CH2N2

nC8H17

HCO2Me

H

(R)-segphos

1) LDA, then PhSeBr 2) NaIO4

nC8H17

HCO2Me

H

H

HDried bean beetle

Hayashi, T. et al. J. Org. Chem. 2005, 70, 5767.Also see, J. Am. Chem. Soc. 2001, 123, 2089.Org. Lett. 2003, 5, 217.

Reactions of Allenes: General Survey

Ma, S. Chem. Rev. 2005, 105, 2829-2871.

Cycloaddition

O

CO2MeOH

OH

CO2Me

O

OH

OH

H

A variety of [4+2], [3+3]cycloaddition reactions

R1

R2

H

CO2Et

Oxidation--Oxo transfer

Versatile substrate for oxidations

R3

RuCl3(cat)

NaIO4R2

CO2EtOH OH

R3

R1

O

TM Catalyzed Addition to Allenes

Various transition metal catalyzedcycloisomerization of allenes

TsNO

H TsNO

O

H

H

Ru3CO12

CO, Et3N

Metal Mediated Ionic Reactions

As a unique substratefor many metallic cations

HO

NMeH

OHBoc

O MeONBoc

H

PdII,AgI, AuI

Activating Metals for Allenes

MNu Nu

MNu = O, N, C, S, X M = Pd, Ag, Au

Pd

Rh, Hg, Cu, Ce, Fp+, etc

Pt

Ag

Au

10 11

More electronegative...more covalent character with C

OS

EN

I

I,III

II,IV

II,IV

2.54

1.932.20

2.28

Natural adundant MoreLess

Oxidation Stateusually II Au I, III are capable of catalizing the same transformation

RedoxRe Ox Re OxX

β-HeliminationYes No, usually proto-demetallation--charateristic!

Hoffmann-Roder, A.; Krause, N. “The Golden Gate to Catalysis” Org. Biol. Chem. 2005, 3, 387-391 and references cited therein.

Regiochemical Courses

Type IIMetal

Nu Nu M = R-PdIIM

Ar-X + Pd(0)PdXAr

Migratoryinsertion

ArPdII

Nu'

Ar

Nu'

Type I MetalNuNu

M M = AgI, AuI,III,PdII

HOn

n = 1,2

O M+

M

HH

δ+

allylic >> vinylic carbocation

H

Endo

O

M

H

+Proto-demetallation (Ag, Au)O

H

5 or 6 rings

n = 3,4

M+ O

M

H

- M

Exo

OM

H

+- M

OH

5 or 6 rings

Ring size

-

δ+

-

Axis to Center Chirality Transfer

Proto-demetallation

Me

MeOH

Me

OTBS

axis chirality

AuCl3

CH2Cl2

OMe Me

OTBSMe

center chirality

(5 mol%)

AgNO3 (80 mol%)

A

A

CaCO3

Complete chirality transferReaction rate: Au(III) >> Ag(I)

OMe Me

Me

CHO

MeCitreoviral

Krause, N. et al. Org. Lett. 2001, 3, 2537; Synthesis 2002, 1759; Org. Lett. 2004, 6, 2141.Also, see review: Arcadi, A. Cur.Org. Chem. 2004, 8, 795.

Marshall, A.J. Org. Chem. 1993, 58, 7180.

Me

OMe

Me

AuCl Cl

ClOTBS

H

δ+OMe Me

OTBSMe

H

+

AuCl

Cl

AuCl3

Cl-

R3R4

XHR1

R2

AuCl3

XR1R3R4

R2

X = N, S

Exo case: Clavepictine A

NAcO

Me

H

nC6H13Clavepictine A

Me OEt

OH

OH

ON

O

CBzTIPSOMe NH

TIPSOMe

H

H

H

nC6H13

OTES

AgNO3

NAg+H

HRH

HMe

OTIPS

N

Me

TIPSO

H

RH H

H

Ag+

N

Me

TIPSO

HH

R

7%

N

HR

HMe

OTIPS

H

48%

H

NTIPSO

Me

H

nC6H13

TESO

Ha, J. D.; Cha, J. K. J. Am. Chem. Soc. 1999, 121, 10012.

Allenyl ketones to Furan

R1

OR3

R2 Rh(I)Ag(I)Au(III) OR1

R2

R3

Marshall, J. A. J. Org. Chem. 1990, 55, 3450.J. Org. Chem. 1995, 60, 3796. Hashmi, A.S.K. Angew. Chem. Int. Ed. 2000, 39, 2285.

Analogue (allenyl acid to furanone)

OR1 R3

M R2

+

H O

HO2C

H

Me

Me

AgNO3

Me

O

O

Me

Me

Me

O

H

Br

ORH

Au(III)Cl3O

R

AuCl3

Br

H

+

-

Br

ORH

Au(I)

OR

Au

Br H

+Et3PCl -

Highlight, Hashmi, A. S. K. Angew. Chem. Int. Ed. 2005, 44, 6990.

Au(I) vs Au(III)Gevorgyan, V. et al. J. Am. Chem. Soc. 2005, 127, 10500.

Br

ORH

Both deactivated

AuCl3 Et3PAlCl

OH

Br

R OBr

H

R

C-C Bond Formation

O

HEt

+

EtCOCl + iPr2NEt

OMe

H

TMSQn (10 mol%)

MgCl2

99% ee (>98%de)

OO

Me

Et

N

MgBr

CuCN

1)

2) TMSCHN2

H

MeO2C Et

N

Me

N

EtMeO2C

Me

NEt

NH

O

catalyst (mol%) dr yield, %

(MeCN)2PdCl2 (30)AuCl3 (10)AuCl3(5), AgOTf (20)Ph3PAuOTf (5)

67:3392:8

97:392:8

83278292

(-)-Rhazinilam

Liu, Z.; Wasmuth, A. S.; Nelson, S. J. Am. Chem. Soc. 2006, 128, 10352.

Et

N

MMeO2C

H

Anti-mode

Pd(II) Mediated Reactions

N

O

HOMe

I5 mol% Pd(PPh3)4

K2CO3 (1.2 equiv)THF, reflux

NN

O

O

IMgBr

HgCl2

O

O

Me

N

O

OMe

H

PdII

B

N

O

OMe

HPdII

I

Nagao, Y.; Jeong, I.-Y. Tetrahedron Lett. 1998, 39, 8677.

Type II

Me

Me

CO2H

H+ CHO

Pd(OAc)2

LiBr, THF, rtOO CHO

Me

Me

CO2H

H

PdIIType I

OO PdII

Me Me

OO CHO

Me MePdII

Liu, G.; Lu, X. Tetrahedron Lett. 2003, 44, 127.

H+

Summary

Synthesis of allenes: The most standard and convenient method for the asymmetric synthesis of allenes is the manipulation of chiral propargylalcohol derivatives, for which recent progress of catalytic asymmetric synthetic methods would provide a wide variety of chiral starting materials.

Reaction of allenes: Allene, a very interesting compound with a hybrid character of an olefin and an acetylene, is a versatile functionality because it is useful as either a nucleophile or an electrophile and also as a substrate for many chemical transformations mediated metal catalysts. This multi-reactivity makes an allene as excellent candidate for many synthetic manipulations.

Outlook: Some recent reports have demonstrated the potential usefulness of axially chiral allenes as synthon. However, methods for supplying the optically pure allenes are still limited. Further novel asymmetric catalysis for the preparation of allenes will certainly be developed. Application of allenes in useful stereoselective synthesis has been made possible by the use of chiralallenes and exciting developments in this field in the near future seem certain.