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哥伦比亚教授有机化学课件Olefination


O lefination R eactions
Lecture Notes

Key Review s:

W ittig Reaction K. C. Nicolaou and co-w orkers, Ann. 1997, 1283. Horner-W adsw orth-Em m ons and Tebbe O lefinations S. E. Kelly, C om prehensive O rg. Synth. 1991, Vol. 1, 729. Peterson O lefination D. J. Ager, Synthesis 1984, 384. Julia (Julia-Lythgoe) O lefination B. M . Trost, Bull. Chem . Soc. Jpn. 1988, 61, 107.

W ittig O lefination: B ackground and Principles
R1 X PPh 3 + R1 X Ph 3 P R1 Ph 3 P pK a = 18-20 w hen R = alkyl, H ylide R1 n-B uLi, LDA , LiH M DS Ph 3 P + O

R1

-[Ph 3 P=O ] strong bond form ation drives reaction

Ph Ph P Ph O R

Ph
1

Ph P

Ph R1

O

oxaphosphatane

betaine

G . W ittig and G . Schollkopf, Chem . B er. 1954, 87, 1318.

W ittig O lefination: B ackground and Principles
Stereoselectivity w ith non-stabilized ylides Me Ph 3 P Me Ph 3 P Ph 3 P Me Ph 3 P OMe Ph 3 P

Not stable; m ust be m ade in situ and used im m ediately

W ittig O lefination: B ackground and Principles
Stereoselectivity w ith non-stabilized ylides Me Ph 3 P Me Ph 3 P Ph 3 P Me Ph 3 P OMe Ph 3 P

Not stable; m ust be m ade in situ and used im m ediately

A ddition to carbonyl is an irreversible and concerted [2+2] cycloaddition such that the R groups on the aldehyde and the ylide are as far apart as possible

PPh 3 + O Ph 3 P Me O R H

H Me R

Ph 3 P O H H

-[Ph 3 P=O ] A s the size of the R groups increases, selectivity for Z-alkene increases N onpolar solvents favor initial addition Polar solvents favor the elim ination Me

Z-alkene

W ittig O lefination: B ackground and Principles
Stereoselectivity w ith stabilized ylides Me O Ph 3 P Ph 3 P O Ph 3 P O Et Me sem istabilized

Incredibly stable; not m oisture sensitive, can be chrom atographed Price for stability is low er reactivity: reacts w ell w ith aldehydes, slow ly w ith ketones

W ittig O lefination: B ackground and Principles
Stereoselectivity w ith stabilized ylides Me O Ph 3 P Ph 3 P O Ph 3 P O Et Me sem istabilized

Incredibly stable; not m oisture sensitive, can be chrom atographed Price for stability is low er reactivity: reacts w ell w ith aldehydes, slow ly w ith ketones Initial addition to carbonyl is reversible so the therm odynam ic elim ination product results. O + O O Et PPh 3 Ph 3 P O H Ph EtO 2 C H m inor kinetic product RDS Ph 3 P O H H EtO 2 C Ph rotation possible EtO 2 C Ph EtO 2 C Ph + Ph 3 P O H H EtO 2 C Ph m ajor kinetic product

therm odynam ically m ost stable; predom inant or only product

W ittig O lefination: A pplications in Total Synthesis
O OH

1. P h 2 P=CH 2 , TH F, -10 ° C
M eO

HO

2. A D-m ix- ? , O M e t-B uO H /H O 2 (84% overall) (96% ee)
W ittig reaction

M eO

OMe

Me HO H 2N O

Me O

HO

OH OH

O O Cl O OH O N H

O HO H N Cl H N O

O

O N H O

H N H NH2 O

H N

N N Br N Br

O

Me Me

1. P CC , C H 2 C l 2 2. P h 3 P=C H 2 , TH F, -20 ° C (86% overall)
W ittig reaction
Br

N N N Br
H O 2C

NH

Me

HO

OH OH

vancom ycin

HO

K . C. N icolaou and co-w orkers, Angew . Chem . Int. Ed. 1998, 37, 2708.

W ittig O lefination: Applications in Total Synthesis

BnO BnO

PPh 3 O

I

BnO BnO

O TBDPS O O O Bn

BnO BnO BnO

O TBDPS O BnO

BnO

PPh 3 I

BnO BnO B nO

1. TBAF BnO O 2. I 2 , PPh 3 3. PPh 3 BnO BnO O BnO O BnO BnO O BnO OMe BnO BnO O OM e

nBuLi, THF, HM PA, O -20 ° 4 h C, BnO (87% ) OMe W ittig reaction

BnO

BnO BnO B nO

These researchers have m ade tetraoses and pentaoses via this technology

A. Dondoni and co-w orkers, J. O rg. Chem . 2002, 67, 4186.

W ittig O lefination: A pplications in Total Synthesis
TB SO Me Me Me Me Me O Me O PM P = p-m ethoxyphenyl Me HO Me O O HO Me Me OH Me O O NH2 Me TB SO A Me Me Me Me PM P Me O Me PPh 3 Me TH F Me O PM P Me Me Me I TB SO Me PPh 3 I Me N aH M D S; then A -78 ° to rt C Z/E = >49/1 (76% ) W ittig reaction Me Me Me Me O Me O O O TB S O SEt PM P TB SO Me Me Me O SEt TB SO O TB S

OH (+)-discoderm olide

A . B . Sm ith and co-w orkers, J. A m . C hem . Soc. 2000, 122, 8654.

W ittig O lefination: A pplications in Total Synthesis
Me OMe OMe Me P Ph 3 B r OMe OMe Me O OH

Me

n-B uLi
TB S O H Me O Me OMe

0 ? ?25 ° C (97% ) (3:1 E/Z) W ittig reaction w ith sem istabilized ylide

TB SO

H

Me OMe Me Me

H O H

Me Me

Me

colom biasin A

K . C . N icolaou and co-w orkers, A ngew . Chem . Int. Ed. 2001, 40, 2482. M . D . Shair and co-w orkers, J. A m . C hem . Soc. 2002, 124, 773.

W ittig O lefination: A pplications in Total Synthesis
Me OMe OMe Me P Ph 3 B r OMe OMe Me O OH

Me

n-B uLi
TB S O H Me O Me OMe

0 ? ?25 ° C (97% ) (3:1 E/Z) W ittig reaction w ith sem istabilized ylide

TB SO

H

Me OMe Me Me

H O H

Me Me

Me

colom biasin A

Me

OH TIPS

1. Dess-M artin [O ] 2.
Ph 3 P M e , THF I TIPS I

Me

M eO

O TBS

(47% overall) W ittig reaction

O

fragm ent for longithorone A

K . C . N icolaou and co-w orkers, A ngew . Chem . Int. Ed. 2001, 40, 2482. M . D . Shair and co-w orkers, J. A m . C hem . Soc. 2002, 124, 773.

W ittig O lefination: A pplications in Total Synthesis
Me H O Me H H O O O H H O H H Me H H O Me Me Me O H

O TM S + PPh 3 I

EtS EtS O
H O

H

O

O TB S Me

H

H

O

O TP S

(75% ) W ittig reaction TB S O Me H O Me Me H EtS Me O TM S O H H Me H O O EtS O H O H O O H H Me H H O O H H H Me HO n-B uLi, H M PA , TH F, -78 ° C
Me H O O O H H O H H H O H Me Me brevetoxin B O Me Me H O H H O O H H O H

O TP S

O

H

H O

Me Me O

K . C . N icolaou and co-w orkers, J. A m . C hem . Soc. 1995, 117, 1171. For a review , see: C lassics in Total Synthesis I, C hapter 37.

W ittig O lefination: A pplications in Total Synthesis

O TB D PS

1. DIBAL-H, THF, -78 ° 5 h C, 2. Ph 3 P
OMe ,

O TBD PS

1. Ph 3 P, DEA D, (PhO ) 2 P(O )N 3
OH

O TB DP S

O

O

THF, 0 ° C (75% overall) W ittig R eaction

M eO

2. 5 N HCl, THF/ CH 2 C l2 (1:4) (74% overall)

N3 O

This chain extension technique is usually good yielding as long as the m olecule is acid stable

+

OMe OMe OMe N OH N H N HO N3 O TB DPS

THF, -78 ° C (70% )
N

( ? )-quinine

G . Stork and co-w orkers, J. A m . C hem . Soc. 2001, 123, 3239.

W ittig O lefination: A pplications in Total Synthesis
Me Me O Me H O H OMe
OMe

O 3 , C H 2 Cl 2 / M eO H (3:1), -78 ° 10 m in; C, M e 2 S, 20 ° 16 h C, (98% )

Me

O

O

Ph 3 P

Me

O O OMe

H

OMe

toluene, 110 ° 3 h C, (84% ) W ittig reaction
Me

Me HO Me OMe O OH Me HO Me O O O O Me Me O HO OH

O Me

HO Me M eO

O

Me OH Me Me OH

sw inholide A
OMe

I. Paterson and co-w orkers, Tetrahedron 1995, 51, 9393.

W ittig O lefination: A pplications in Total Synthesis
O NH2 OH N H Boc

1. (B oc) 2 O 2. TB DPSCl
O TB D PS

H ,

CHO

N HB oc O TB D PS

(69% overall)

Br

C O 2M e PP h 3

CH 2 Cl 2 , ?
N N H p-TsO H N NH2 H N O TB D PS H OH C O 2M e Br

(91% ) (12:1 ratio of Z/E isom ers) W ittig reaction
Br

TM SO Tf, 2,6-lutidine; then p-TsO H (85% )

C O 2M e NH B oc O TBD PS

m anzam ine A S. F. M artin and co-w orkers, J. A m . C hem . Soc. 1999, 121, 866.

W ittig O lefination: B ackground and Principles
Schl ?sser-m odified W ittig R eaction: H ow to G et E-products w ith N on-stabilized Ylides

+ O

PhLi, TH F, -78 ° C IPh 3 P Me

Me

Ph 3 P O H H

M . Schl ?sser, A ngew . C hem . Int. Ed. Engl. 1966, 5, 126.

W ittig O lefination: B ackground and Principles
Schl ?sser-m odified W ittig R eaction: H ow to G et E-products w ith N on-stabilized Ylides

+ O

PhLi, TH F, -78 ° C IPh 3 P Me

Me

Ph 3 P O H H

PhLi (1 equiv), -30 ° , 5 m in C

Ph 3 P O Me Me H

H

Ph 3 P O HCl Me

H

M . Schl ?sser, A ngew . C hem . Int. Ed. Engl. 1966, 5, 126.

W ittig O lefination: A pplications in Total Synthesis
Me PPh 3 + O Me

O

O Me PPh 3 I PhLi, TH F

O

O Me

O

O

O

O

PhLi (1 equiv); then M eO H , -30 ° C (97:3 trans:cis)

Schl?sserm odified W ittig reaction
Me

O Me Me H O progesterone H H Me H

Me O O Me

O

O

W . S. Johnson and co-w orkers, J. A m . C hem . Soc. 1970, 92, 741. For a review , see: C lassics in Total Synthesis I, C hapter 6.

W ittig O lefination: A pplications in Total Synthesis

O 3, M eO H
(98% )
M eO

OMe O

1. EtPPh 3 I/n-BuLi; n-BuLi; acid 2. p-TsO H, acetone (65% overall) Schl?sser-m odified W ittig reaction
O Me

O O O O HO OH H Me O O Me CO O H O O O O

O Me

O O

Me CO O H

CP-225,917 (phom oidride A )

C P-263,114 (phom oidride B)

K . C. N icolaou and co-w orkers, Angew . Chem . Int. Ed. 1999, 38, 1669.

Horner-W adsw orth-Em m ons O lefination: Background and Principles
O + Cl O Et O

O R O PX RO X = Li, K, N a

THF, -78 ° C

O RO P RO

O O Et

?
neat Arbuzov reaction Cl

OEt

+

P(O R) 3

Horner-W adsw orth-Em m ons O lefination: Background and Principles
O + Cl O Et O

O R O PX RO X = Li, K, N a

THF, -78 ° C

O RO P RO

O O Et

?
neat Arbuzov reaction Cl

OEt

+

P(O R) 3

Stereoselectivity Principles: Follow s general rules of stabilized ylides O NaH + O O O (RO ) 2 P H EtO 2 C O H Ph EtO 2 C OEt P(OR ) 2 O (RO ) 2 P H EtO 2 C O Na Ph H + O (RO ) 2 P H EtO 2 C ON a H Ph

m inor kinetic product RDS Ph

m ajor kinetic product

rotation possible

therm odynam ically m ost stable; predom inant or only product

EtO 2 C

Ph

Horner-W adsw orth-Em m ons O lefination: A pplications in Total Synthesis
Me M e 3 Sn O TB D PS O + M e O A c M eM e Pd 2 dba 3 , LiC l, i-Pr 2 N Et, N M P, 35 ° C Me Me O TB DPS Me Me O

? -A llyl Stille R eaction
(single stereoisom er) (96% )

N M P = N -m ethyl-2-pyrrolidinone

1. H IO 4 , N aIO 4 , TH F/H 2 O 2.
O Me O EtO P E tO

(92% overall) HW E O lefination

t-B uO K , TH F

Me Me Me Me Me H O Me Me Me Me Me OH palom inol O TIPS O (E-isom er only) O TB D PS

S. A . Snyder, E. J. C orey, J. A m . Chem . Soc. 2006, 128, 740.

H orner-W adsw orth-Em m ons O lefination: A pplications in Total Synthesis
OH TESO Me N OMe O Me

1. TM SC l, im id 4-D M A P, C H 2 C l2 TE SO 2.
Li O P OMe OMe M eO M eO

O TM S Me

O P O

TH F, -78 ° C
O

B a(O H ) 2 , THF; A TH F/H 2 O (40:1), 0 ° C
H

I Me

(83% ) HW E olefination

A
O TM S

Me H

H O

O H HO H

Me H OH

HO

Me

O I Me

O Me

H H Me

( ? )-FR 182877
E. J. Sorensen and co-w orkers, J. A m . C hem . Soc. 2003, 125, 5393.

H orner-W adsw orth-Em m ons O lefination: A pplications in Total Synthesis
OBn OH

1. B nB r, K 2 C O 3 , K I, D M F, 25 ° C 2. K O H ,
O O Et P O Et O O Et O OEt

N aO H , t-B uO C l, B nO C O N H 2 , (D H Q D ) 2 A Q N ,

OBn HO O O Et

O

(93% overall)
H W E olefination

K 2 O sO 2 (O H ) 4 , n-PrO H /H 2 O (1:1), 25 ° , 12 h C (45% , 87% ee) Sharpless asym m etric am inohydroxylation

NH Cbz

TB SO Tf, 2,6-lutidine, C H 2 C l 2 , 0 ° , 30 m in C
Cl OH TB SO O O Et OH

(98% )

OBn

SO 2 C l 2 ,
NH2

TB SO O OEt

H 2, Pd(O H ) 2 /C ,
NH 2

TBSO O O Et

Et 2 O /C H 2 C l 2 (1:10), 0 ° , 1 h C (80% )

M eO H , 25 ° C (97% )

NH Cbz

vancom ycin fragm ent K . C . N icolaou and co-w orkers, A ngew . C hem . Int. Ed. 1998, 37, 2708.

H orner-W adsw orth-Em m ons O lefination: A pplications in Total Synthesis

Me OH CHO

Me

1. Br Me K 2 CO 3 , acetone 2.
O E tO P EtO CO 2 Et

O C O 2 Et

1. DIBAL-H, C H 2 C l2 2. Sw ern [O ] (90% overall)

O CHO

OMe

N aH , TH F (91% overall) H W E olefination

OMe

OMe

ZnC l 2 , CH 2 C l 2 , (60% ) Diels-A lder 25 ° 3 days C, reaction
Me H H C O 2H O OMe H H CHO OMe Me O

HO

O

HN

HO

O

HO

dynem icin A S. J. D anishefsky and co-w orkers, J. A m . C hem . Soc. 1996, 118, 9509.

H orner-W adsw orth-Em m ons O lefination: A pplications in Total Synthesis
O P(O M e) 2 Br O N O N C bz O TB S Pd(dppf)Cl 2 , K 2 CO 3 , D M E, 90 ° C (60% ) Suzuki coupling O O Sterics dictates this product
NH

O O N Cbz O TBS P(O M e) 2 N O NM O M

+

N MOM

M eO B O

M eO 1. HF, M eCN, 0 ° C 2. 2,2-DM P 3. Dess-M artin [O ] O

O

(70% )

O N Cbz

O
Me

N O NMOM

Me

N Me

N

N Cbz

Me

O

P(O M e) 2 N O NM O M

LiCl, D M F, 70 ° C (60% ) HW E M acrocyclization M eO O

M eO

O

diazonam ide A core K. C . Nicolaou and co-w orkers, J. Am . Chem . Soc. 2002, 126, 10162. For a related use of 1,1,3,3-TM G , see: S.J. Danishefsky, et al. J. Am . C hem . Soc. 2001, 123, 1890.

H orner-W adsw orth-Em m ons O lefination: A pplications in Total Synthesis
C O 2M e O P
M eO OMe Me

M eO O M e

N aH , benzene, 15-crow n-5 25 ° , 5 h C (55% ) H W E dim erization
Me

C O 2M e
Me HO OH

HO

OH

O

C O 2M e
Me HO Me HO OH

HO Me

OH OH Me

( – )-cylindrocyclophane A
T. R . H oye and co-w orkers, J. A m . C hem . Soc. 2000, 122, 4982.

H orner-W adsw orth-Em m ons O lefination: A pplications in Total Synthesis

Me TB SO Me

O TH P Me O

1. EtO EtO P O LD A , TH F 2. D IB A L-H 3. M nO 2 (86% overall) H W E olefination

C O 2 Et TB SO

Me

O TH P Me O

Me

EtO EtO P O LD A , TH F

C O 2 Et H W E olefination

Me RO Me

OH Me O R = TB S 1. PPTS, M eO H RO 2. D IB A L-H 3. M nO 2

Me

O TH P Me C O 2 Et R = TB S

Me

(48% overall)

K . C . N icolaou and co-w orkers, J. A m . C hem . Soc. 1988, 110, 4672. For a review , see: C lassics in Total Synthesis I, C hapter 24.

H orner-W adsw orth-Em m ons O lefination: A pplications in Total Synthesis
O TB S Me TB SO Me OH Me O HO O + Me Me Me Me (M eO ) 2 P O 1. D C C , 4-D M A P 2. D B U , LiC l, C H 3 C N , 25 ° C (70% overall) H W E m acrocyclization O O O O O OMe O O TB S C O 2M e

O TB S Me TB SO Me O Me O OR OR OR OR

OMe O

O TB S C O 2M e

O core architecture of am photericin B

K . C . N icolaou and co-w orkers, J. A m . C hem . Soc. 1988, 110, 4672. For a review , see: C lassics in Total Synthesis I, C hapter 24.

Horner-W adsw orth-Em m ons O lefination: Background and Principles

Me B nO O B nO

Me CO 2 R E-alkene B nO

Me

C O 2R

Z-alkene

O Ph 3 P OMe M eO M eO P O i-PrO i-PrO P O O LiHM D S, TH F, -78 ° C OMe O O Et 19 1 3 1 C H 2 C l2 , 0 ° C 7 1

LiH M D S, TH F, -78 ° C

Y. K ishi and co-w orkers, Tetrahedron 1981, 37, 3873.

H orner-W adsw orth-Em m ons O lefination: Background and Principles

Me BnO O B nO

Me CO 2 R E-alkene BnO

Me

CO 2 R

Z-alkene

O Ph 3 P OMe M eO M eO P O i-PrO i-PrO P O M eO M eO P O O LiHM D S, THF, -78 ° C OMe O O Et O KO t-Bu, THF, -78 ° C OMe 1 3 19 1 Use of non-hindered phosphonate, low tem p., and KO t-Bu can favor Z-olefin Enhances rate of elim ination relative to equilibration 3 1 CH 2 C l 2 , 0 ° C 7 1

LiHM DS, TH F, -78 ° C

Y. K ishi and co-w orkers, Tetrahedron 1981, 37, 3873.

Horner-W adsw orth-Em m ons O lefination: Background and Principles
O + Cl O Et O

O R O PX RO X = Li, K, N a

THF, -78 ° C

O RO P RO

O O Et

?
neat Arbuzov reaction Cl

OEt

+

P(O R) 3

Stereoselectivity Principles: Follow s general rules of stabilized ylides O NaH + O O O (RO ) 2 P H EtO 2 C O H Ph EtO 2 C OEt P(OR ) 2 O (RO ) 2 P H EtO 2 C O Na Ph H + O (RO ) 2 P H EtO 2 C ON a H Ph

m inor kinetic product RDS Ph

m ajor kinetic product

rotation possible

therm odynam ically m ost stable; predom inant or only product

EtO 2 C

Ph

H orner-W adsw orth-Em m ons O lefination: Still-G ennari M odification
First M ethod to U se Phosphonates and G et E-A lkenes

O F 3C H 2C O P F 3C H 2C O

O O Et K H M D S, K O t-B u, K H , or K 2 C O 3 w ith 18-C row n-6

W . C . Still, C . G ennari, Tetrahedron Lett. 1983, 24, 4405.

H orner-W adsw orth-Em m ons O lefination: Still-G ennari M odification
First M ethod to U se Phosphonates and G et E-A lkenes

O F 3C H 2C O P F 3C H 2C O

O O Et K H M D S, K O t-B u, K H , or K 2 C O 3 w ith 18-C row n-6

Stereoselectivity Principles: C hanges the R D S from the elim ination to the initial addition O + O O O Et P(O R ) 2 O K base RDS (R O ) 2 P H EtO 2 C ONa Ph H + O (R O ) 2 P H EtO 2 C ONa H Ph

m inor kinetic product

m ajor kinetic product

EtO 2 C

Ph EtO 2 C Ph predom inant or only product

W . C . Still, C . G ennari, Tetrahedron Lett. 1983, 24, 4405.

Still-G ennari M odified H W E O lefination: A pplications in Total Synthesis
K H M D S, 18-C row n-6, toluene Me O TH P (89% ) Still-G ennari m odified H W E olefination

O F 3C H 2C O P F 3C H 2C O C O 2M e +

O

C O 2M e Me O TH P

O F 3C H 2C O P F 3C H 2C O C O 2B n +

TB S N O

O

K 2C O 3, 18-C row n-6, toluene (65% ) Still-G ennari m odified H W E olefination B nO 2 C

TB S N

O

S. V. Ley and co-w orkers, J. C hem . Soc., PT 1 1999, 1917. E. J. Thom as and co-w orkers, J. C hem . Soc., PT 1 1999, 1083.

Still-G ennari M odified H W E O lefination: A pplications in Total Synthesis
O F 3 C H 2 CO P F 3 C H 2 CO C O 2M e sugarO TB SO Br M eO 2 C O Me

sugarO TB SO O Br O

Me

K HM D S,18-Crow n-6, TH F, -78 ° C (57% ) Still-G ennari m odified H W E olefination

sugarO H TBSO Br H

H

W hat reaction w as used to m ake the core? Me

M eO 2 C

O

tricyclic core of spinosyn A

W . R. R oush and co-w orkers, O rg. Lett. 2002, 4, 3157.

Still-G ennari M odified H W E O lefination: A pplications in Total Synthesis

O TB DPS O N O O B oc N O O Me Me P O F 3C H 2C O F 3C H 2C O O Me O O K 2C O 3, 18-C row n-6 toluene, -40 ° 5 h C, (77% ) Boc Z:E = 4:1 N StillG ennari O m odified H W E olefination O O N O O Me O O Me Me core structure of phorboxazole A

O TB DPS

C. J. Forsyth and co-w orkers, J. A m . Chem . Soc. 1998, 120, 5597.

Julia-Lythgoe O lefination: A Versatile M ethod for Form ing E-A lkenes
O Ph B ase (usually LD A or LiH M D S) O S R1

O O S R1

Ph + Li O

O R2 O S R1

Ph R2 OH

A c2O

O O S R1 H

Ph R2 OAc

M . Julia, J.-M . Paris, Tetrahedron Lett. 1973, 4833.

Julia-Lythgoe O lefination: A Versatile M ethod for Form ing E-A lkenes
O Ph B ase (usually LD A or LiH M D S) O S R1

O O S R1

Ph + Li O

O R2 O S R1

Ph R2 OH

Form s the m ost stable radical prior to quenching, w hich ultim ately affords E-alkene products

A c2O

O R1 R2 R1 O S R2 R1

O Ph R2 N a/H g in M eO H O S R1 H

Ph R2 OAc OMe

M . Julia, J.-M . Paris, Tetrahedron Lett. 1973, 4833.

Julia-Lythgoe O lefination: A pplications in Total Synthesis
O O O TB S N Teoc SO 2 Ph Li Me Me N Teoc H SO 2 Ph A cO Me Me Teoc = (2-trim ethylsilyl)ethoxycarbonyl Na/H g O 1. H IO 4 2. TPA P 3. TB AF (22% overall) O TBS N Teoc H Julia olefination (77% ) O TBS

H

TH F, -78 ° C; Ac 2 O O

O

OH N

H

Me indolizom ycin Me

Me Me

S. D. Danishefsky and co-w orkers, J. A m . C hem . Soc. 1993, 115, 30.

Julia-Lythgoe O lefination: A pplications in Total Synthesis
TESO M e HO O Me TESO PhO 2 S O t-B u Si t-B u O O Me O TES OH Me H Me O D EIPS Me TB SO O O O OH Me Me H TESO O PM B O TES Me O t-B u Si t-B u O OMe Me O O TES + Me D EIPSO Me TB SO Me H O O Troc O O Me H O PM B 1. LiN Et 2 2. A c 2 O (66% ) 3. N aH C O 3 , M eO H -TH F; N a/H g Julia-Lythgoe olefination

O Me O TES fragm ent en route to cytovaricin

O

OMe Me O TES

D . A . Evans and co-w orkers, J. A m . C hem . Soc. 1990, 112, 7001.

K ocienski-M odified Julia-Lythgoe O lefination: A O ne Step Procedure
N N N Ph R1 altered piece Base (usually LDA or LiH M D S) O O S R1 Li N N N N N Ph + O R2 O O S R1 N Ph R2 O Li N N

O O S

N

S N

Also a viable aryl sulfone grouping

A ffords E-alkene products only in one-pot; kinetically controlled, irreversible addition gives anti- ? -alkoxysulfones P. K ochienski and co-w orkers, Synlett. 2000, 365.

K ocienski-M odified Julia-Lythgoe O lefination: A O ne Step Procedure
N N N Ph R1 altered piece Sm iles rearrangem ent Base (usually LDA or LiH M D S) O O S R1 Li N N N N N Ph + O R2 O O S R1 N Ph R2 O Li N N

O O S

N

S N

Also a viable aryl sulfone grouping

N LiO O S R1 O

N N N Ph R2

A ffords E-alkene products only in one-pot; kinetically controlled, irreversible addition gives anti- ? -alkoxysulfones P. K ochienski and co-w orkers, Synlett. 2000, 365.

K ocienski-M odified Julia-Lythgoe O lefination: A O ne Step Procedure
N N N Ph R1 altered piece Sm iles rearrangem ent Base (usually LDA or LiH M D S) O O S R1 Li N N N N N Ph + O R2 O O S R1 N Ph R2 O Li N N

O O S

N

S N

Also a viable aryl sulfone grouping

N N R1 R2 + N Ph N N + SO 3 LiO O S R1 O

N N N Ph R2

A ffords E-alkene products only in one-pot; kinetically controlled, irreversible addition gives anti- ? -alkoxysulfones P. K ochienski and co-w orkers, Synlett. 2000, 365.

Julia-Lythgoe O lefination: A pplications in Total Synthesis
O TB S O TB S O O O TB D PS LiH M D S, D M F, -35 to 0 ° C O TB S O TB S O O TB D PS Me OH OH O C O 2H Me Me (+)-am bruticin Me Me O Me Me Me Me O Me + N N Ph N N S O O O Me

Me Me Me Me K ocienski m odified (30:1 E/Z) Julia-Lythgoe olefination

E. N . Jacobsen and co-w orkers, J. A m . C hem . Soc. 2001, 123, 10772.

Julia-Lythgoe O lefination: A pplications in Total Synthesis
O TB S O TB S O O O TB D PS LiH M D S, D M F, -35 to 0 ° C O TB S O TB S O O TB D PS Me OH OH O C O 2H Me Me (+)-am bruticin Me ? Me O Me Me Me Me O Me + N N Ph N N S O O O Me

Me Me Me Me K ocienski m odified (30:1 E/Z) Julia-Lythgoe olefination

E. N . Jacobsen and co-w orkers, J. A m . C hem . Soc. 2001, 123, 10772.

Julia-Lythgoe O lefination: A pplications in Total Synthesis
N N N N Ph O OMe O TESO + Me Me TESO N aH M D S, H M PA , D M E, -78 ° C (35% ) K ocienski m odified Julia-Lythgoe olefination Me Me

O O S

O OMe

Me Me

Me

Me

Me

OH

O Me Me

O callystatin A OMe

A . B. Sm ith and co-w orkers, O rg. Lett. 2001, 3, 1685.

Julia-Lythgoe O lefination: A pplications in Total Synthesis
N N N N Ph O OMe O TESO + Me Me TESO N aH M D S, H M PA , D M E, -78 ° C (35% ) K ocienski m odified Julia-Lythgoe olefination Me Me

O O S

O OMe

Me Me

Me

Me

Me

OH

O Me Me

Also m ade by a sim ilar olefination

O callystatin A OMe

A . B. Sm ith and co-w orkers, O rg. Lett. 2001, 3, 1685.

Tebbe O lefination: Background and Principles

Me (C p) 2 Ti Cl Al Me

THF 0° C

THF (C p) 2 Ti C H 2 60 ° C

Me (Cp) 2 Ti Me Petasis R eagent

Tebbe R eagent

Tebbe reagent is com m ercially available ($454.50 for 100 m L of a 0.5 M solution in toluene) B y contrast, sim ple ylide sells for pennies per gram

Reacts w ith virtually every carbonyl (w hich other m ethods do not do at all).

F. N. Tebbe, J. A m . Chem . Soc. 1978, 100, 3611. N. A . Petasis, J. A m . Chem . Soc. 1990, 112, 6392.

Tebbe O lefination: A pplications in Total Synthesis
O TB S O Me N O O Me B oc C p 2 Ti(M e) 2 (5.0 equiv) toluene, 70 ° C (81% ) Me N O O Me B oc O TB S

I. M artinez, A . H . H ow ell, Tetrahedron Lett. 2000, 41, 5607.

Tebbe O lefination: A pplications in Total Synthesis
O TB S O Me N O O Me B oc C p 2 Ti(M e) 2 (5.0 equiv) toluene, 70 ° C (81% ) Me N O O Me B oc O TB S

G eneral Trend of Functional G roup R eactivity A cids A lcohols A ldehydes K etones A m ides Esters Functional group reactivity Epoxides can som etim es survive; but tend not to be tolerated. N ote: Surprises are som etim es observed in highly functionalized cases.

I. M artinez, A . H . H ow ell, Tetrahedron Lett. 2000, 41, 5607.

Deoxygenation of Sulfoxides Using Tebbe Reagent: Discovery of a Novel Titanocene-M ethylidene M ediated Process
O N Cbz O H 2 C=PPh 3 THF, -78 ° C, 1 m in O Br O N C bz O O N C bz

PPh 3

(99% ) BnO PhS O BnO O Br O Br

B nO PhS O

K .C. Nicolaou, A .E. Koum bis, S.A. Snyder, K.B. Sim onsen, Angew . Chem . Int. Ed. 2000, 39, 2529.

Deoxygenation of Sulfoxides Using Tebbe Reagent: Discovery of a Novel Titanocene-M ethylidene M ediated Process
O N Cbz O H 2 C=PPh 3 THF, -78 ° C, 1 m in O Br O N C bz O O N C bz

PPh 3

(99% ) BnO PhS O O N Cbz Cp Ti O O Cp N Cbz BnO O Br O Br

B nO PhS O O N Cbz

O

Tebbe Reagent (2.2 equiv) TH F, -20 ° C, 0.5 h

- O Ti(Cp) 2
(73% ) BnO PhS

BnO PhS O

O

Br

BnO PhS O

O

Br

O

Br

K .C. Nicolaou, A .E. Koum bis, S.A. Snyder, K.B. Sim onsen, Angew . Chem . Int. Ed. 2000, 39, 2529.

Tebbe O lefination: A pplications in Total Synthesis

H N

O

O O

C p 2 Ti(M e 2 ), THF, ? , 24 h (87% ) Tebbe-Petasis olefination

H N

O O

O

N Me

O

N Me

H N W ittig reaction did not succeed w ith the substrate O

O

N Me

gelsem ine

D . J. H art and co-w orkers, J. A m . C hem . Soc. 1997, 119, 6226.

Tebbe O lefination: A pplications in Total Synthesis

TM SO O

O O TB S

Tebbe reagent, TH F, 4-D M A P, -40 ° C (71% ) Tebbe olefination

TM SO

O O TB S

1. TB A F 2. (H SiM e 2 ) 2 N H , N H 4 C l 3. Pt(D VS) 2 ; H 2 O 2

Intram olecular hydrosilation

Br Me

O OH

HO OH

O OH

laurencin

A . H . H olm es and co-w orkers, J. A m . C hem . Soc. 1993, 115, 10400.

Peterson O lefination: B ackground and Principles

M e 3 Si

R1

R1 acid (anti) M e 3 Si R1 R2 base (syn) R2

R2 base (syn) M e 3 Si HO acid (anti) R1 R2

M e 3 Si

R1

HO

O

R1

R2

M e 3 Si HO

R1 R2 N onstabilized Peterson reagents usually add w ith no diastereoselectivity, so hard to get E- and/or Z-selectivity; stabilized Peterson reagents are m ore controlled and typically give Z-olefins under basic reaction conditions

D . J. Peterson and co-w orkers, J. O rg. C hem . 1968, 33, 780. D . J. Peterson and co-w orkers, J. A m . C hem . Soc. 1975, 97, 1464.

Peterson O lefination: A pplications in Total Synthesis

(i-Pr) 3 Si TBSO O O Me (83% ) Peterson olefination (i-Pr) 3 Si TB A F, THF (93% ) Si(i-Pr) 3 n-B uLi, -74 ° to 25 ° , 8 h C C TB SO O Me

Cl O CC l 4 , PPh 3 Me toluene, 65 ° , 12 h C (92% )

HO O Me

brasilenyne

S. E. Denm ark, S.-M . Yang, J. A m . Chem . Soc. 2002, 124, 15196.

Peterson O lefination: A pplications in Total Synthesis

Me Me TB SO Me O

M e 3 Si

C O 2M e

TB SO

Me Me Me

(C y) 2 N Li, TH F, -78 ° to -25 ° C C Peterson olefination

C O 2M e

Me Me TB SO N o other m ethod gave the Z-alkene needed for the synthesis Me Me lancifolol Me

H . M onti and co-w orkers, Tetrahedron Lett. 2001, 42, 6125.

Peterson O lefination: A pplications in Total Synthesis

O Me M eO 2 C CN O Me Me O CN

D M SO , H 2 O , 155 ° 4 h C, Transannular Diels-Alder reaction

Me H O H Me Me Peterson olefination (71% )

Boron serves to m ask the anionic species Me

B (O i-Pr) 2 TH F, -78 ° C M e 3 Si CN

OH Me

CN

CN

Me H HO H Me Me m aritim ol O

H H Me Me

A. Toro, P. N ow ak, P. D eslongcham ps, J. Am . C hem . Soc. 2000, 122, 4526.

Peterson O lefination: A pplications in Total Synthesis
O Me O Me H O Me O O TM S OBz O H TM S Li Me H O Me O O TM S O H OH O OH TM S Me

TH F, -78 ° , C 10 m in (48% )
N o other procedure w orked for this olefination

49% aq. HF, M eCN , 25 ° C

Peterson olefination (83% overall)

Me O Me H O Me O OH O O H O OMe Me OH O O TM S O Me H O O H OH Me

resiniferatoxin

P. A . W ender and co-w orkers, J. A m . C hem . Soc. 1997, 119, 12976.

O ops, I M ade the W rong A lkene: O lefin Inversion Reactions
m C B PA Ph O H Ph Ph H Ph 2 PLi H O Li Ph

Ph

Ph PPh H 2

E. Vedejs and co-w orkers, J. A m . C hem . Soc. 1971, 93, 4070.

O ops, I M ade the W rong A lkene: O lefin Inversion Reactions
m C B PA Ph O H Ph Ph H Ph 2 PLi H O Li Ph

Ph

Ph PPh H 2

M eI

Ph Ph

Me -[Ph 2 M ePO ] (95% , 99% cis) Ph 2 P O Ph Ph H H H

O Li Ph

Ph PPh H 2 Me

E. Vedejs and co-w orkers, J. A m . C hem . Soc. 1971, 93, 4070.

O ops, I M ade the W rong A lkene: O lefin Inversion Reactions
m C B PA Ph O H Ph 1. m C PB A 2. Ph 2 PLi 3. M eI Ph H Ph 2 PLi H O Li Ph

Ph

Ph PPh H 2

M eI

Ph Ph

Me -[Ph 2 M ePO ] (95% , 99% cis) Ph 2 P O Ph Ph H H H

O Li Ph

Ph PPh H 2 Me

E. Vedejs and co-w orkers, J. A m . C hem . Soc. 1971, 93, 4070.

O ops, I M ade the W rong A lkene: O lefin Inversion Reactions
m C B PA Ph O H Ph 1. m C PB A 2. Ph 2 PLi 3. M eI Ph H Ph 2 PLi H O Li Ph

Ph

Ph PPh H 2

M eI

Ph Ph

Me -[Ph 2 M ePO ] (95% , 99% cis) Ph 2 P O Ph Ph H H H

O Li Ph

Ph PPh H 2 Me

Me Me

1. m CPB A Me 2. Ph 2 PLi 3. M eI Me (85% ) O TH P

1. m C PB A 2. Ph 2 PLi 3. M eI O THP (90% )

E. Vedejs and co-w orkers, J. A m . C hem . Soc. 1971, 93, 4070.

O ops, I M ade the W rong A lkene: O lefin Inversion R eactions
O KH, 18-C row n-6 Me Me Me Me O xy-C ope rearrangem ent (75% ) H Me O Me

OH

O O O O O O

175 ° , toluene C 4 ? -conrotatory electrocyclic ring opening

(82% )

18-crow n-6 O O O O Me Me h? O lefin isom erization
+

O Me Me

Me

Me periplanone B

S. L. Schreiber, C . Santini, J. A m . Chem . Soc. 1984, 106, 4038. For a review , see: C lassics in Total Synthesis I, C hapter 21


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