Total Synthesis of (-)-Quinocarcin

Stoltz. J. Am. Chem. Soc., 2008, 130 (51), 17270-17271Myers. J. Am. Chem. Soc., 2005, 127 (48), 16796-16797Zhu. J. Am. Chem. Soc., 2008, 130 (22), 7148-7152

李楠

2009.04.20

N

O

NMe

OMe

H

CO2H

A B C

D

E

(-)-Quinocarcin

inhibition of lung canceractivity against lymphocytic leukemia etc.

N

O

NMe

OMe

H

CO2H

1

NNMe

OMe

H

CO2H

OOH

N

OMe

H

OOBn

NCbz

OTIPS

Br

N

OH

O

NHCbz

OTIPSOBn

Br

OMe

HNH

CO2Me

OBnOMe

Br

HO2C

NHCbz

OTBS

CHO

OH

CHO

OBn

NCO2tBuPh

Ph

10

12

11

8

9

46

7

Zhu's total synthesis of (-)-Quinocarcin

J. Am. Chem. Soc., 2008, 130 (22), 7148-7152

intramolecularnucleophilic attack

intermolecular condensation

Pictet-Spenglerreaction

alkylation

install the labile oxazolidine ring

Br Br

OTBS

Ph2C=NCH2CO2tBu (11)

15 ( 0.1 eq ), CsOHCH2Cl2, -78oC

TFA/AcOH/H2O ( 1:1:1 )

Br

CO2tBu

NH2

OTBS

TBAF

THF

Br

CO2tBu

NH2

OH

H

Br

CO2tBu

NH2

OH

H

OBn

CHO

17 12

17

4A MS, AcOH

CH2Cl2 NH

CO2tBu

H3

H1

Br

OHOBn

NOE correlation betweenH1/H3:1, 3-cis

20

16

effectively obviated the regioselectivity

(a). Boc2O, DIPEA, MeCN

(b). Me2SO4, acetone,Cs2CO3 NBoc

CO2tBu

H

H

Br

OMeOBn

SOCl2

MeOHNH

CO2MeH

H

Br

OMeOBn

21 8

N

H

H

Br

OMeOBn

O

NCbz

OH

SEt

N

H

H

Br

OMeOBn

O

NCbz

N

H

H

Br

OMeOBn

O

NCbz

O

EtSH

Hf(OTf)4

Hf(OTf)4

EtSH

Hf(OTf)4

PhSH

25

O

A

26

N NN

N

OHHOAt

N NN

N

ON(CH3)2

N(CH3)2

PF6

HATU

mixture of two diastereomers (ratio 3/2)

NH

CO2MeH

H

Br

OMeOBn

8

HOOC

NHCbz

OTBS

HATU, HOAt

DIPEA, DMF

9

N

H

H

Br

OMe

22

OBnO

CO2MeNHCbz

OTBS

N

H

H

Br

OMe

22

OBnO

NHCbz

OTBS

LiBH4, MeOHEt2O

OH

Swern oxidation

N

H

H

Br

OMeOBn

O

NCbz

OTBS

OH

24Strong nucleophile

weak nucleophile

N

H

H

Br

OMeOBn

O

NCbz

OH

SEt

25

(a) Swern oxidation

(b) TIPSOTf,Et3NN

H

H

Br

OMeOBn

O

NCbz

SEt

OTIPS

27

N

H

H

Br

OMeOBn

NCbz

O

CHO

AgBF4,THF

28

Jonesoxidation

N

H

H

Br

OMeOBn

N-Cbz

O

COOH

35

E/Z = 8/1

deprotection under one-pot condition

(a) Pd/C, H2, MeOH

(b) HCHO, HCOOH NaBH3CN

N

H

H

OMeOH

NMe

O

COOH

Li/NH3then 2N HCl

4

N

O

NMe

OMe

H

CO2H

A B C

D

E

(-)-Quinocarcin

NFmoc

H

O

OBnOH

H

O

N

CNH2N

TMS

O

N

CNNH

TMS

NH

OHOBn

HCN

Na2SO4

DBU; HCN

N

NH

OH

HH

CNH

OBn

ZnCl2, TMSCNTFE, 60oC, 15h

12

3

4

Myers's total synthesis of (-)-Quinocarcin

key step : allyl silane-imine addition

C DN

N

OH

H

CNOBn

TMS

O

O

Fmoc

N

N

OMe

HH

CNH

OBn

OH

Me

O

1. Cs2CO3, Me2SO480%

2. NaIO4, OsO4, 88%3. Jones Reagent, 91%

5

AgNO3

MeOH, H2O70% ( 2 steps) N

N

OMe

HH

H

OH

Me

O

O

A B C D

(-)-Quinocarcin

J. Am. Chem. Soc., 2005, 127 (48), 16796-16797BCl3: Lewis acid capable of selective cleavage of ether and acetal protecting groups

BCl3N

N

OMe

HH

CNH

OH

OH

Me

O

DX-52-1 ( 6 )

N

NH

OH

HH

CNH

OBn

4

C D

N

MeN

O

OAr

OH electrocyclicring-opening

N

NMeO

OAr

OH COOH

exo-si

1,3-dipolar cycloaddition

N

MeN

O

O

COOH

Ar

OH

N

MeN

COOH

O

MeO

Quinocarcin

Garner ' s strategy

J. Am. Chem. Soc. 1992, 114, 2767–2768J. Am. Chem. Soc. 1993, 115, 10742–10753

N

N

O

H

OOH

Me

OMe

N

N

OOMe

Bn

OMeO

OMeOBn

AryneAnnulation

OMe

O NH

N

OOMe

Bn

OOMe

Quinocarcin (1) 9

+

BnO

10 11

HN

N

OOMe

Bn

O

12

Stoltz's total synthesis of (-)-Quinocarcin

HN

N

O

Bn

BrN

SO

O

+

1. N-Me-morpholine MeCN, -20oC

2. NaOMe, MeOH, 23oC

( 74% yield, 2 steps )13 14

O

HN

NBn

OOMe

O

12 (11:1 separable cycloadducts)

BnO

O

Cl 15

DMAP, Et3N

CH2Cl223oC reflux

( 93% yield )

N

NBn

OOMe

OO

BnO

16

Y(OTf)3, MeOH

CH2Cl2, reflux

( 69% yield )

NH

NBn

OOMe

O

BnOO

OMe11

auxiliary-controlled dipolar cycloaddition

Screened Zn(OTf)2, Sc(OTf)3, and Sm(OTf)3, and none provided enamine 11 in greater than 40% yield.

NH

NBn

OOMe

O

BnOO

OMe11

OMe

TMS

OTf+

17

TBAT

THF, 40oC

( 60% yield )

N

NBn

OOMe

OOMeOBn

OMe

9

Pd/CH2 ( 1atm )

THF, 23oC

3.3 : 1 dr18a : 18b

NH

NBn

OOMe

OOMeOBn

OMe

NH

NBn

OOMe

OOMeOBn

OMe

18a

18b

5

5

NaBH3CNconcd HCl

MeOH, 0oC

aryen annulation reaction

Si

Ph

FPh

FPh N

Bu

Bu BuBu

TBAT

NH

NBn

OOMe

OOMeOMe

NH

NBn

OOMe

OOMeOBn

OMe

19a ( 55% yield from 9 )

H

H

11a

11a

19b ( 17% yield from 9 )

OBn

toluene

110oC

(99% yield from 19a)

N

NBn

OOMe

OOMeOBn

H

20

Selectivelycondensed

aq HCHOPd(OH)2/CH2(1atm)

MeOH, 23oC

( 80% yield )

N

NMe

OOMe

OOMe

H

OH21

LiOH H2O

THF/H2O 23oC

N

NMe

OOH

OOMe

H

OH 22

Li, NH3(l), THF

-78oC -30oC then 1N HCl

81% yield, 2 steps

N

NMe

OOH

OMe

H

O

(-)-Quinocarcin

10% overall yield11 steps (shortest synthesis to date)

N

HN O

R1RHal

NR

HN O

R1-H+

NR

N O

R1

1 2 3

NMe

N O OOMe

NMe

N O

OMe

O 54

NMe

N O

+H+, -H+

4a

NMe

HN O

OMe

O6

Arkivoc. 2007 (xvi) 51-57

1, 3 - Dipolar Cycloadditions to Oxidopyriziniums

Y

X X

-X-

slow

H+

fastH

XX=halogen, Y=H or halogen

SiMe3

OTf

F-

-FSiMe3 OTf

H+

slow

-OTf-

fast

H

OTf

TMS

OTMS

n-Buli TMS

OLi

Tf2O

1.2eq 2 eq

SiMe3

OTf

SiMe3

OTf

F- FuranO

Kobayashi, H. Chem. Lett. 1983, 12, 1211–1214.

J. AM. CHEM. SOC. 2005, 127, 5340-5341

TMS

OTfOEt

O O

CsF(2.5 eq)

MeCN(0.2M)

80oC, 1.5 h

+

OEt

O O

+

Cs

CO2Et

O CsO

Me

RO

OEt

Cs

H+

O

EtO O1 2

34

5a, R = Me5b, R = H

753% yield

OEt

O O

Ph

642% yield

H+

Benzyne C-C insertion reactions

TMS

OTf

R NH

O

COOCH3

+F-

N

RO

COOCH3

COOCH3

NO

R

NCOOCH3

OR

Indolines

N

R

COOCH3

Isoquinolines

J. Am. Chem. Soc., 2008, 130 (5), 1558-1559

formal [3+2]

[4+2]

Synthesis of Indolines and Isoquinolines via Aryne Annulation

NH2

CHO

CO2H

O

N

CO2H

NH2

O H

NH

OH

H

-H2O

N

H

N

H

O

CO2H

H

NH

OCO2HH

H+

NH

CO2HOH2H

-H2O

NH

CO2H

air oxidation

-2H N

CO2H

Doebner reaction

Liebigs. Ann. Chem. 1887, 242, 256.

NH

CO2HHHO

Pictet-Spengler Reaction :The most popular procedure used to close the tetrahydroisoquinoline ring system

R1O

R1ONH2

+O

HR2

HCl

NH

R

R1O

R1O

R1O

R1ONH2

O

HR2

HR1O

R1OHN

R2

OH

H+ R1O

R1OHN

R2

OH2

-H2OR1O

R1ON

R2

H

R1O

R1ONH

HR2

R1O

R1ONH

HR2

NH

R

R1O

R1O

Ber. Dtsch. Chem. Ges. 1910, 44, 2030

Pictet-Gams Reaction

HN

R

O

OH

P2O5N

R

HN

R

O

OHP O P

O

OO

OHN

R

O

OH

P

O

O NH

OH

HR OPO2

N

R

OH

P O PO

OO

O

N

R

OPO2

HB

N

R

Ber. Dtsch. Chem. Ges. 1910, 43, 2384

HN

R

OPOCl3

N

R

HN

R

OP

O

Cl Cl

Cl

-Cl-

HN

R

OPOCl2

NH

ROPOCl2

NH

R OPOCl2H

Cl

N

R O PO

ClCl

H

Cl

N

R

HCl O PO

Cl

Bischer-Napieralski Reaction

Ber. Dtsch. Chem. Ges. 1893, 26, 1903-1912

Baldwin规则：由于不同类型反应的分子轨道重叠不同，因此特定组合的闭环反应具有相应得禁阻和允许性质。但含正离子和第二周期元素的反应通常不符合该规则。环中的原子个数，一般为 3-8；以 exo和 endo表示闭环时断键的位置，环内对应 endo,环外对应 exo;以 tet,trig和 dig表示反应中亲电碳的杂化状态， tet对应 sp3杂化， trig对应sp2杂化， dig对应 sp杂化。例：

O

OMe

O

5-endo-trigO

OMe

O1

2

34

5

0% 100%

5-exo-trigO

O