me · 2016. 12. 24. · total synthesis of khusimone! oppolzer et al. j. am. chem. soc., 1982, 104,...

MacMillan Group Meeting!5-20-09!

by!

Anthony Casarez!

H !

Me

H

!Me

Kurt Alder!

!" Born: Königshütte, Upper Silesia in southern Poland, on the 10th of July 1902.!

!" Education: Began chemistry at the University of Berlin in 1922 then finished his PhD in 1926 at the University of Kiel for work supervised by Otto Diels.!

!" Notable Award: Nobel Prize in Chemistry (1950) with Otto Diels for the 4 + 2 cycloaddition (Diels-

Alder) discovered in 1928. !

A Pericyclic Reaction!

Alder, K.; Pascher, F.; Schmitz, A. Ber. Dtsch. Chem. Ges. 1943, 76, 27.!

!" Direct translated quote: !

!“It is concluded that the addition occurs at the carbon atom adjacent to the double bond (ene). During the course of the reaction a hydrogen atom is detached and transposed to the region of the

maleic acid anhydride (enophile).”!

O

O

O

!O

O

O

H

!" Dr. Alder was unaware that his discovery was mechanistically very similar to the Diels-Alder which

would later win him the Nobel Prize.!

Mechanistic Comparison!

!" Diels-Alder! !" Alder-Ene!

HOMO

LUMO

O

O

O

O

O

O

!

HOMO

LUMO

H

O

O

O

H!

O

O

O

!" Normally, both transformations occur with the HOMO of the diene/ene and the LUMO of the

dienophile/enophile. Lewis acids also work to catalyze the Alder-ene reaction.!

In the Beginning!

!" Thermal Alder-ene!

Huntsman et al. J. Org. Chem., 1962, 27, 1983.!

Me

Me457 °C

35%

Me

Me457 °C

35%

MeMe

In the Beginning!

Huntsman et al. J. Org. Chem., 1962, 27, 1983.!

Me

490 °C

25%

Me Me

Me

400 °C

82%

CO2Me CO2Me

!" Thermal Alder-ene!

The Metallo-Ene!

!" Type I!

Cl

MeMe

Mg, THF, 80 °C

PhNCO, 86%

NHPh

O

!" Type II!

Felkin et al. Tetrahedron Lett., 1972, 22, 2285.!

MgBr Me

ether, reflux

67%

Oppolzer et al. J. Am. Chem. Soc., 1982, 104, 6476.!

The Metallo-Ene!

!" Type I!

Cl

MeMe

Mg, THF, 80 °C

PhNCO, 86%

NHPh

O

!" Type II!

Felkin et al. Tetrahedron Lett., 1972, 22, 2285.!

Mg

Me

Mg

Me

PhNCO

MgBr Me

ether, reflux

67%

The Metallo-Ene: M = Mg, Li, Zn!

Type I!

Ring formation: 5 > 6 >> 7!

Selectivity: syn ring juncture!

Heterocycles: problematic!

Type II!

Ring formation: 6 > 5 # 7 >> 8!

Selectivity: syn ring juncture!

Heterocycles: when M = Zn!

X

Me

XMe

Me

Me

"M" "M"

Total Synthesis of Khusimone!


O

Me

Me

CO2Et

LDA, THF, -78 °C

then allyl-Br, -40 °C, 50%

O

CO2Et

Me

HOOH

1. TsOH,

2. NaOEt, EtOH, 74%

97%CO2Et

Me Me

H

O

O1. LAH, ether, 92%

2. MsCl, pyr, then LiCl (aq) 51%

Me Me

H

O

O

Cl

Mg0, THF, 60 °C

then CO2, -10 °C, 82%

OO

H

H Me

Me

CO2H

!" Can the diastereoselectivity be accounted for?!

Transition State Analysis!


!" Chair conformation

experiences the least

steric interaction!

H

MgCl

Me

Me

OO

H

OO

H

H

MgCl

ClMg

Me

MeHH

OO

OO

H

H

MgCl

X

Total Synthesis of Khusimone!


O

Me

Me

CO2Et

LDA, THF, -78 °C

then allyl-Br, -40 °C, 50%

O

CO2Et

Me

HOOH

1. TsOH,

2. NaOEt, EtOH, 74%

97%CO2Et

Me Me

H

O

O1. LAH, ether, 92%

2. MsCl, pyr, then LiCl (aq) 51%

Me Me

H

O

O

Cl

Mg0, THF, 60 °C

then CO2, -10 °C, 82%

OO

H

H Me

Me

1. LAH, THF, 92%

2. MsCl, TEA, CH2Cl2, then1 N HCl (aq)/ether, 93%

H

H Me

Me

O

CO2HOMs

t-BuOK, t-BuOH/PhH

98%H Me

Me

O

(+)-Khusimone9-steps, 11% overall yield

The Catalytic Metallo-Ene: M = Zn!

Marek et al. J. Org. Chem., 1995, 360, 863.!

TBAF

KF

Me

OH

Me

OSithexMe2

OSthexMe2

SiMe3nBuLi, THF, -70 °C

ZnBr2, warmed to 20 °C then HCl, 80%

Me

OSithexMe2

SiMe3

H •

SiMe3

ZnBr

RO OSithexMe2

SiMe3

ZnBr

!" Product can be differentially desilated.!

The Catalytic Metallo-Ene: M = Zn!

Marek et al. J. Org. Chem., 1995, 360, 863.!

TBAF

KF

Me

OH

Me

OSithexMe2

OSthexMe2

SiMe3nBuLi, THF, -70 °C

ZnBr2, warmed to 20 °C then HCl, 80%

Me

OSithexMe2

SiMe3

R

SiMe3

nBuLi, THF, -70 °C

ZnBr2, warmed to 20 °C R

SiMe3

ZnBr

I2

HCl

R

Me

R

R = CH2t-Bu

I

R = Me

!" Product can be differentially desilated.!

!" Alkyl-Zn can be hydrolyzed or trapped with electrophiles.!

!" Can also be used directly in cross-coupling reactions.!

Tandem Zn Promoted 1,2-Brook Rearrangement Metallo-Ene!

Marek et al. Org. Lett., 2009, ASAP.!

t-But-Bu

OH

N

OH

L =

H •

R

ZnBr

Me3SiO OSiMe3

R

ZnBr

Me3SiO

ZnEt

(CH2)3CH=CH2

R

O

SiMe3

1. ZnEt2, 20 mol% L* Tol, rt, 12 h

2. THF, 40 °C, 24 h3. HCl, TBAF

Me

OH

RHR R = Ph, 92%, >99:1 dr, 81:19 erR = Hex, 91%, >99:1 dr, 77:23 er

Tandem Zn Promoted 1,2-Brook Rearrangement Metallo-Ene!

Marek et al. Org. Lett., 2009, ASAP.!

t-But-Bu

OH

N

OH

L =

O

SiMe3


2. THF, 40 °C, 24 h3. HCl, TBAF

Me

OH

RHR R = Ph, 92%, >99:1 dr, 81:19 erR = Hex, 91%, >99:1 dr, 77:23 er

O

SiMe3


2. THF, 40 °C, 24 h3. HCl, TBAF

OH

RHPh

SiMe3

Me3Si

79%, 77:23 er

The Catalytic Metallo-Ene: M = Ni!

Oppolzer et al. Tetrahedron Lett., 1988, 29, 6433.!

36 h

58%

!" The same trends are observed for Pd.!

AcO

TsN Ni(COD)2, dppb (10 mol%) rt, 6 h, 88%

TsN

H

H

NTs

NiIITHF

AcO

TsN Ni(COD)2, dppb (10 mol%)

TsN

H

H

NTs

NiII

THFX

The Catalytic Metallo-Ene: M = Pd!


AcO

E E

AcO

E E

AcO

Cl

SN2

!-ally-Pd

Pd(PPh3)4, AcOH

70 °C, 72%

E E

Pd(PPh3)4, AcOH

70 °C, 80%

E E

H

H

H

H

The Catalytic Metallo-Ene: M = Pd!


AcO

E E

AcO

E E

AcO

Cl

SN2

!-ally-Pd

!" Also works to form cis or trans decalin systems:!

Pd(PPh3)4, AcOH

70 °C, 72%

E E

Pd(PPh3)4, AcOH

70 °C, 80%

E E

H

H

H

H

H

H

E EH

H

E E

or

Stereochemistry of Pd-Catalzed Metallo-Ene!

Oppolzer, W. Pure & Appl. Chem. 1990, 62, 1941.!

!" Terminal olefin results in loss of stereochemical integrity.!

!" E-alkene allows for transfer of stereochemistry.!

BocN

OAc

Pd(PPh3)4

AcOH, 70 °C

BocN

Pd

BocN

Pd

64%

BocN

(S)

racemic

BocN

Me

OAc

Pd(PPh3)4

AcOH, 70 °C

BocN

Me

Pd

BocN

Me Pd

H

64%

BocN

Me

H(S)(S)

> 99% ee

Stereochemistry of Pd-Catalzed Metallo-Ene!

Oppolzer, W. Pure & Appl. Chem. 1990, 62, 1941.!

!" Alkene geometry impacts expected outcome.!

76%

BocN

Me

H(R)

97% ee

BocN

OAc

Pd(PPh3)4

AcOH, 70 °C

BocN

Pd

BocN

Pd

(S)

Me

MeMeH

anti-!-allyl

BocN

Pd

MeH

BocN

Me

Pd

syn-!-allyl

Doing More in One Step!

Oppolzer et al. Tetrahedron Lett. 1989, 30, 5883.!

TsN

I

Ni(COD)2/dppb (25 mol%)

THF/MeOH 4:1CO (1 atm), rt

TsN

H

NiIILn

H

80%

TsN

H H

ONiIILn

TsN

H H

O

MeO2C

!" CO-insertion happens at both alkyl-Ni stages!



TsN

I

Ni(COD)2/dppb (25 mol%)


TsN

H

NiIILn

TsN

H

ONiIILn

87%

TsN

H

O

MeO2C

TsN

I

Ni(CO)3/PPh3 (25 mol%)


TsN

NiIILn

TsN

MeO2C

69%

!" Changing the ligand allows for control of CO-insertion.!



TFAN

AcO

Pd(dba)2/PPh3 (10 mol%)

AcOH, CO (1 atm)45 °C

TFAN

H

PdIILn

H

TFAN

H

CO2H

H

H2O

CH2N2, CH2Cl2

TFAN

H

CO2Me

H

70%

!" Pd-affords the trans-ring juncture.!

Models for Diastereoselectivity!


NiII

H

H

TsN

L

L

PdII

H

H

L

LTFAN

!" Endo! !" Exo!

TFAN

H

CO2Me

H

TsN

H H

O

MeO2C

The Catalytic Metallo-Ene: M = Rh!

Oppolzer, W.; Furstner, A. Helv. Chim. Acta 1993, 76, 2329.!

X! n! Yield (%)!

NTs! 1! 80!

NTFA! 1! 83!

NCbz! 1! 63!

C(CO2Me)2! 1! 75!

C(SO2Ph)2! 1! 88!

NTs! 2! 65!

C(SO2Ph)2! 2! 55!

X

AcO

RhH(PPh3)4/P[Ph(OMe)3]3 2 mol% 4 mol%

AcOH, 80 °C

X

n n

PdII-Catalyzed Formal Alder-Ene!

Trost, B. M.; Lautens, M. J. Am. Chem. Soc. 1985, 107, 1781.!

EE

E

C6D6, 60 °C, 85%

Pd(OAc)2(PPh3)3 (5 mol%)E

EE

H

H

!" PdII is necessary for catalysis. !

!" Can be performed in one pot.!

OAcE

12 h, Then PdII, reflux 1.5 h, 68%

Pd(PPh3)4, NaH, THF, refluxE

EE

H

HE

E



!" 1,4-Diene observed with no allylic substitution outside of pendant ring.!

!" A trans-relationship results when allylic substitution exists inside the pendant ring.!

C6D6, 60 °C, 68%


E

E

E

MeMe

H

(CH2)8CH(OMe)2 C6D6, 60 °C, 71%


E

E

E

(CH2)8CH(OMe)2

Mechanistic Proposal!


E

E R'

R

PdII PdIVE

E

RR'

HH

!"H elim.

!"H elim.

E

E

R R'

PdIV

H

E

E

R R'

PdIV

H

E

E

R R'

E

E

R R'

red.

elim.

red.

elim.

H

H

PdII

PdII



!" 1,3-Diene observed with allylic substitution outside of pendant ring.!

C6D6, 66 °C, 64%

Pd(OAc)2(PPh3)3 (5 mol%)

E

EE

E

C6D6, 66 °C, 71%


E

EE

EO

O

O

O

C6D6, 66 °C, 80%


E

EE

E R

Me

Me

R

Mechanistic Support for Palladacycle Pathway!

R

E

E

Pd

CO2Me

CO2MeMeO2C

MeO2C

PPh3, C6H6, 60 °C

E

E

E

E

R

R = Me, 59%, 2 : 3R = H, 54%

E

E

E

E

CO2Me

CO2Me

E

E

CO2Me

CO2Me

not

Pd

CO2Me

CO2MeMeO2C

MeO2C

P(o-OTol)3, 60 °C

CO2MeMeO2C

, DCE

Me

Me

Pd

CO2Me

CO2MeMeO2C

MeO2C

P(o-OTol)3, 60 °C, 83%Me

Me

CO2MeMeO2C

CO2Me

CO2Me Crossover expmt withCO2EtEtO2C

shows only acetylene incorporation.

, DCE

Trost, B. M.; Tanoury, G. J. J. Am. Chem. Soc. 1987, 109, 4753.!

Mechanistic Support for Palladacycle Pathway: Remote Binding!

Trost et al J. Am. Chem. Soc. 1994, 116, 4255.!

Cat!n = 1!

A:B!Yield!

n = 2!

A:B!Yield!

Pd(OAc)2! 21:1! 76! 1.1:1! 75!

Pd(OAc)2[P(o-Tol)3]2! >20:1! nd! 1:1.6! 74!

Pd(OAc)2(PPh3)2! 2.7:1! nd! 1:4.6! 81!

Pd(OAc)2(PPh3)3! 1:2.3! 24!

E

E

E

ECat

n

n

BA

E

E

n

PdIV

HaHb

Hb

PPh3


!" No reaction observed w/o AcOH!


AcOH (5 mol%), rt, TOTP (5 mol%)

Pd2dba3CHCl3 (2.5 mol%), C6D6

Me

MeTBSO

Me

TBSO

Me

TBSO

88%, 7.5 : 1


!" No reaction observed w/o AcOH!




Me

MeTBSO

Me

TBSO

Me

TBSO

88%, 7.5 : 1



R

R

E

E

E

E

95% 75%

c-Hex

E

E

86%

E

E

OMeMeO

E

E

OAcAcO

!" Sensitive functional groups also tolerated!



E

E

R'R

PdIIH

OAc

E

E R'

R

E

E

R'R

PdIIOAc

E

E

R R'

PdII

H

H

E

E

R R'

Pd0 + AcOH

H-PdII-OAc

Predominent Product

Mechanistic Support for Hydro-Palladation Pathway!


E

E

R R'

PdII

H

H

AcOH (1 eq), rt, TOTP (5 mol%), PMHS

Pd2dba3CHCl3 (2.5 mol%), C6H6

R

R

E

E

E

E

96% 75%

c-Hex

E

E

E

E

OAcAcO

AcOH (5 mol%), rt, AsPh3 (5 mol%)

OPd2dba3CHCl3 (2.5 mol%), CH2Cl2O

Ph

Ph

Ph

20%

Ph



E

E

R R'

PdII

H

H

AcOH (1 eq), rt, TOTP (5 mol%), PMHS


R

R

E

E

E

E

96% 75%

c-Hex

E

E

E

E

OAcAcO

rt, AsPh3 (5 mol%)

OPdOAc2(AsPh3)2 (5 mol%), CH2Cl2O

Ph

Ph

Ph

96%

Ph



E

E

PdIIOAc

E

E

R R'

PdII

H

H

AcOH (1 eq), rt, TOTP (5 mol%), DSiEt3


R

E

E

E

E D

AcOD (1 eq), rt, TOTP (5 mol%), PMHS


R

E

E

E

E

D

A Much Cheaper Alternative: Fe!

Furstner et al. J. Am. Chem. Soc. 2008, 130, 1992.!

XCH2R

2

R3

Fe0 Li O

O

Toluene, 90 °C

(5 mol%) 1

XR1

R1

H

R3

R2

Me

H

EE

97%, 6:1 trans/cis

Me

H

EE

93%, 5.8:1 trans/cis5 mol% 2

TsN

n-Pr

H

90%, 7.9:1 trans/cis

EE

80%

TsN

79%

Me

H

EE

97%, 6.3:1 trans/cis5 mol% 2

p-OMe-Ph

nn

On-Pr

H

82%, 20:1 trans/cis20 mol% 2

Ph

EE

79%, 15 mol% 1

A Much Cheaper Alternative: Fe!


Fe0 Li N

N

Toluene, 90 °C

X

H

H

R

m

n

XH

R

m n

H

H

p-OMe-Ph

EE

50%, 10 mol% 2

(5 mol%) 2

H

HPh

EE

93%

TsN

H

HPh

60%, 10 mol% 2

Ph

E EH

H

68% 2.5:1 cis/trans10 mol% 2

Ph

EEH

H

63

Ph

EEH

H

95%

Me

EEH

H

93%

EEH

H

93%

Divergent Pathways to Observed Sterochemistry!


!" Pseudo-axial approach affords cis-diastereomer!

!" Pseudo-equatorial approach affords trans-diastereomer!

trans!

cis!

H

Fe

E

E

R H

HR

EE

E E

R

H

Fe

H

R

E

E

R

EEH

H

R

E E H

HFe

E

E

Fe

H

H

R

R

E

E

Expectation of D-Labeling Study!


Ph

E E

D

syn to D

anti to D

Ph

E E

HFe

D

Ph

EE

DFe

Ph

EE

D

Ph

E E

DFe

H Ph

E E

DFe

H

Ph

EE

HFeD

FePh

DH

EE

H

Ph

EE

DFeH

H

Ph

EE

HD

Ph

EE

DH

Ph

E E

HFe

D

H



Scrambling!

Ph

E E

D

syn to D

anti to D

Ph

E E

HFe

D

Ph

EE

DFe

Ph

EE

D

Ph

E E

DFe

H Ph

E E

DFe

H

Ph

EE

HFeD

FePh

DH

EE

H

Ph

EE

DFeH

H

Ph

EE

HD

Ph

EE

DH

Ph

E E

HFe

D

H



Scrambling!

D-Transfer!

Ph

E E

D

syn to D

anti to D

Ph

E E

HFe

D

Ph

EE

DFe

Ph

EE

D

Ph

E E

DFe

H Ph

E E

DFe

H

Ph

EE

HFeD

FePh

DH

EE

H

Ph

EE

DFeH

H

Ph

EE

HD

Ph

EE

DH

Ph

E E

HFe

D

H

!" If the metallacycle is the pathway for the

trans-ring juncture then deuterium should

be transferred.!



E E

Ph

D

H

Fe

H

D

EE

Ph

Ph

EE

HFe

D

Ph

EE

H

D

!" If the metallacycle is the pathway for the cis-ring juncture then hydrogen should be transferred.!

The Dramatic Conclusion!


!" Deuterium labeling study supports a metallacyle intermediate.!

Ph

E E

D

Fe0 Li N

N

Toluene, 90 °C, 90%

(10 mol%) 2

HPh

EE

DH

E E

R

D

H

Fe0 Li N

N

Toluene, 90 °C, 82%

(10 mol%) 2

R

EE

H

D

Intermolecular Rh-Catalyzed Alder-Ene!

Brummond et al J. Am. Chem. Soc. 2002, 124, 15186.!

!" First report of high yield and selectivity to form cross-conjugated trienes.!

TsN

•

R2

Rh(CO)2Cl2 (2 mol%)

Toluene, rt

TsN

R2

TsN

C5H11

90%, 6:1 E/Z

TsN

93%

R1

R1

TsN

85%, 5:1 E/Z

C5H11

TMS

Intermolecular Rh-Catalyzed Alder-Ene!

Brummond et al J. Am. Chem. Soc. 2002, 124, 15186.!

!" Will This work with ene-allenes?!

Rh(CO)2Cl2 (5 mol%)

Toluene, rt

TsN

•

C6H13

TsNMe

C5H11

TsN

C7H15

or

TsNRhIII

C6H13

Intermolecular Rh-Catalyzed Cycloisomerization!

Brummond, K. M.; Chen, H.; Mitasev, B.; Casarez, A. D. Org. Lett. 2004, 6, 2161.!

!" Tetrahydroazepines are formed instead.!

Rh(CO)2Cl2 (5 mol%)

Toluene, rt

TsN

•

C6H13

TsN

C6H13

!" Product possessed interesting unsaturation for further functionalization.!

Intermolecular Rh-Catalyzed Cycloisomerization!

!" Selected azepine products!

Brummond, K. M.; Chen, H.; Mitasev, B.; Casarez, A. D. Org. Lett. 2004, 6, 2161.!Brummond, K. M.; Casarez, A. D. unpublished work.!

TsN

R3

R1

Rh(CO)2Cl2 (5-10 mol%)TsN

•

R3

R1

TsN

t-Bu

Me

Solvent, reflux

95%, DCE

TsN

t-Bu

SiMe2Bn

97%, DCE

TsN

t-Bu

Ph

95%, 1,4-Dioxane

TsN

Si(i-Pr)3

73%, 5.8:1 E/Z, 1,4-Dioxane

TsN

Me

85%, 1,4-Dioxane

Me TsN

t-Bu

86%, 1,4-Dioxane

Me

R2

R2

TsN

t-Bu

78%, 1,4-Dioxane

TsN

Si(i-Pr)3

69%, 1,4-Dioxane

Me

Two Plausible Mechanisms!

Me

N•

t-Bu

MeD

D

Ts

N •t-Bu

D

Ts

Rh-D

MeN

t-Bu

MeD

Rh-D

Ts

Rh(I) TsN

t-Bu

D

D

Me

N

Rh

Ts

H

H t-Bu

D

D

N

t-Bu

MeD

Rh-D

Ts

path A

path B

89%

Brummond, K. M.; Chen, H.; Mitasev, B.; Casarez, A. D. Org. Lett. 2004, 6, 2161.!

Intermolecular Ru-Catalyzed Alder-Ene!

Trost, B. M.; Toste, F. D. Tetrahedron Lett. 1999, 40, 7739.!Trost et al J. Am. Chem. Soc. 2002, 124, 10396.!

RuCp(MeCN)3PF6 (10 mol%)

DMF, 84%

MeO2C

7 Ph

NHBoc

MeO2CPh

NHBoc

7

!" Selectivity for the branched diene can be high depending on substrate!

!" Selectivity for the branched diene can be high depending on substrate!

OTroc

RuCp(MeCN)3PF6 (5 mol%)

Actone, 85%

OTBS

Me

MeO

OTroc

Callipeltoside ATBSO

OMe

Me 22 longest linear46 overall steps

The Catalytic Cycle!


RuI

NNN

TBSO

OMe

Me

OTroc

RuI

OTroc

TBSO

MeO

Me

S

RuIII OTroc

TBSO

OMe

Me

H

RuIII

TBSO

OMe

Me

OTroc

H

S

OTBS

Me

MeO

OTroc

H

S

Intermolecular Co-Catalyzed Alder-Ene!

Hilt, G.; Treutwein, J. Angew. Chem. Int. Ed. 2007, 46, 8500.!

Etn-Pr

Ph

89%, 8:1 E/Z

MeSiMe3

EtO2C

99%, 99:1 E/Z

Me

EtO2C

95%, 8:1 E/Z

OMe

OMe

n-Pr

99%, 99:1 E/Z

OMe

MeO

EtOTMS

Ph

95%, E only

Et

Ph

80%, 4:1 E/Z

B(pin)

Co(dppp)Br2 (10 mol%)R2 R

2

R1

R3Zn, ZnI2 (20 mol%), CH2Cl2

R1

R3

Other Ene Reactions!

!" The Carbonyl-ene!

Okachi, T.; Onaka, M. J. Am. Chem. Soc. 2004, 126, 2306.!

!" The Imino-ene!

Nakagawa et al. Org. Lett., 2000, 2, 159.!

Ph

Me O

HH

NaY zeolite, cyclohexane

Ph OH20 °C, 94%

Ph

Me NTol

PhH

Yb(OTf)3, TMSCl (5 mol% ea)

Ph NHTolCH2Cl2, rt, 94%

Ph

Other Ene Reactions!

!" The Acetal-ene!

Ghosez et al., Synthesis, 2004, 1375.!

!" The Arynyl-ene!

Ph OMe

OMe FeCl3, CH2Cl2, rt, 95%

Ph

OMe

SiMe3

KF, 18 crown 6

n-Burt, 69%

• n-PrOTf

n-PrHSiMe3

OTf

F-

me · 2016. 12. 24. · total synthesis of khusimone! oppolzer et al. j. am. chem. soc., 1982, 104,...

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