Total Synthesis of Chelidonine and Norchelidonine Via An Enamide - Benzyne - (2+2) Cycloaddi?on Cascade

Total
Synthesis of Chelidonine and Norchelidonine via

An Enamide-‐Benzyne-‐[2+2] Cycloaddi?on Cascade
Zhi-‐Xiong Ma, John B. Feltenberger and Richard P. Hsung Org. Le(, 2012, 14, 2742-‐2745
O
R O
N
H
R O
H
O OH
R = Me, Chelidonine
R = H, Norchelidonine
Current Literature Presenta7on

Jaideep Saha
06.09.2012
Jaideep Saha @ Wipf Group
Benzyne: An Overview
_________________________________________________________________________
benzyne
  A possible existence of benzyne was considered by WiCg in a reac7on of fluoro
benzene with phenyl lithium in 1942.
  J. D. Roberts first proposed the structure of benzyne in 1953.
  Till date, over 75 natural products have been synthesized that u7lized
func7onalized arynes to generate key intermediates in the synthesis.
J. Am. Chem. Soc. 1953, 75, 3290

Chem. Rev. 2012, ASAP

Arynes and related molecules: Structure and Reac7vity
_________________________________________________________________________
Geometrical angel versus hybridiza7on angel
(CO)6Co2
Cycloheptyne stable
t1/2 < 1 min ( -25oC)
t1/2 ca. 60 min ( -76oC)
Eur. J. Org. Chem. 2008, 6053.
Bond Energy: Acetylene 76 Kcal/ mol

Cyclohexyne 35 Kcal/ mol
Org. Le(. 2011, 13, 5937
F
F
O
RHN
O DIFO-R
PNAS, 2007,104, 16793
Angew.Chem. Int. Ed. 2012, 51, 3766

Different methods for the prepara?on of Benzyne
_________________________________________________________________________
X N2 N
N
N
CO2
NH2
X = halogen
4
Na
)
Ac
NH Heat
(O
liq
Pb
NH 2 or
BS
3
N
Ph
I N
TBAF 0oC
N
TMS S
O
O
OTf
TMS
J. Am. Chem. Soc. 1953, 75, 3290
Angew.Chem. Int. Ed.1965, 4, 239
Tetrahedron. 2000, 56, 1013
Chem.Le(. 1983, 1211

Classifica?on of the Reac?on Manifolds:
_________________________________________________________________________
1.  Synthe7c strategies involving nucleophilic addi7on onto arynes.
2.  Strategies based on Inser7on reac7on.
3.  Cycloaddi7on Reac7ons.
4. Mul7component Reac7ons.

Nucleophilic addi?on : Synthesis of Domes?cin and Amurine
_________________________________________________________________________
MeO
MeO
N
N NaO Me
HO Me NaNH2
O
NH3 (l)
O Br -40oC O
O
o-addition p-addition
O
MeO MeO
Me
N N
HO Me
O O
O O
Amurine ( 1.9%) Domesticine ( 6.3%)
J. Chem. Soc. C. 1971, 2712.

Heterocycles. 1976, 4, 1013
Benzocyclobutane via Intramolecular Nitrile Acyla?on: Applica?on in the
Synthesis of Estradiol
_________________________________________________________________________
CN
NaNH2
CN R CN
R Br NH3 (l) R
-33oC
R
R
R R R
CN CN
-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐
H Ot-Bu
CN
1,2-dichlorobenzene
H
MeO MeO
Ot-Bu OH
H H
H H H H
MeO HO
Estradiol
( 84%)
J. Am. Chem. Soc. 1978, 10, 6218

Carbon-‐Carbon Bond Inser?on of Benzyne
_________________________________________________________________________
Nu Nu
Nu E E
O
O O
Br NaNH2
+ +
THF
45-67oC (7:3)
OTMS (56-75%)
( 7:1)
Mechanism:
O
O O O O
Br base
+
Me
J. Am. Chem. Soc. 1994, 116, 9471

_________________________________________________________________________
Acyl-‐Alkyla?on of Aryne
O
TMS O O CsF O O
+ +
OEt OEt
OTf MeCN/ 80oC Ph
( 42%) EtO O
( 53%)
Cs
O
Cs O O O Me
Cs
+
OEt Me
CO2Et O
OEt
J. Am. Chem. Soc. 2005, 127, 5340

_________________________________________________________________________
O
Substrate scope: O O O
O O
OMe
OMe
OEt
TMS
----------------------------------------------------------------------------------------------
OTf O O
O
CO2Me O
O OMe
OMe
( 50%) ( 69%) ( 61%)
Applica7on in the Enan7oselec7ve Synthesis of (-‐) Curvularine

OBn O OH O
OBn O
TMS CsF H2, Pd-C
O
BnO HO
BnO OTf MeCN/ 80oC (60%)
O
( 30%) O O O O
(-) Curvularin
Org. Le(. 2010, 12, 1612

_________________________________________________________________________
Addi?on of Urea O
Me
TMS O N
CsF
Me Me
+ N N
OTf 20oC R N
R
Me
OMe Ph TMS
TMS TMS
Me OTf
OTf OTf
O
Me ----------------------------------------------------------------------------------------------------------------------
N
N Me Ph O O Me
MeO O Me Me
Me N
N N
N
N Me N Me N
N
Me Me O Me
Me
(77%) (66%) (73%)
1:1
Angew.Chem. Int. Ed. 2002, 41, 3247
-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐
Addi?on of Amide
TMS H NH
N CF3 CsF
+
R OTf O MeCN-rt CF3
O
J. Am. Chem. Soc. 2005, 127, 13112

Metal Mediated Func?onaliza?on/ Inser?on Reac?ons of Benzyne
_________________________________________________________________________
Difference in reac?vity of mono and bis π-‐allylpalladium complexes
X
Pd X = OAc, halide Pd
Ln
Nu Nu---E
Electron deficient system, Electron sufficient system,

Electrophilic in nature Act as an amphiphile
TMS Pd2 (dba)2. dppf, CsF

+ SnBu3 + Cl
R OTf CH3CN R
R SnBu3 + Cl
R
R
Org .Le(. 2008, 10, 2393

Tet. Le(. 2000, 41, 729
_________________________________________________________________________
Mechanism for bis allyla?on of aryne
Cl
Pd(0)
Pd X
Pd
Ln
SnBu3
Pd
Bu3SnCl

_________________________________________________________________________
cat. [{!-C3H5 }PdCl]2
O
OMe dppe, CsF OMe O
OAc
TMS +
CO,
OTf CH3CN, 80oC, 4h OMe

56% ( 2.5:1)
O
O
Me TMS Me
+
Me
OTf
66 % ( 1: 1.3)
Mechanism:
O
Pd(OAc)Ln Pd(OAc)Ln CO Pd(OAc)Ln
O O
Pd(OAc)Ln -PdLn
-HOAc
J. Am. Chem. Soc. 2001, 123, 12686

Aryne Annula?on by Cycloaddi?on Reac?on
_________________________________________________________________________
Bu4NPh3SiF2 ( TBAT)
TMS CO2CH3
N CO2CH3 N
OTf O R R Indolines
O
+ F
R R
O O
N N Isoquinolines
R N CO2CH3
H CO2CH3
CO2CH3
J. Am. Chem. Soc. 2008, 130, 1558

Aryne Annula?on by Cycloaddi?on Reac?on
_________________________________________________________________________
R OH R
R = CH3 87%
TMS O N R = n-Bu 76%
N
+ R = Bn 72%
R N CO2CH3 CO2Me R = CF3 57%
OTf H CO2Me
H CH3 R = i-Pr 66%
H X
N N
X = CH2 ( 66%)
O X X=O (66%)
CO2CH3
CH3
CO2CH3
H N
N ( 71%)
-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐
Synthesis of Papaverine
CO2CH3
CO2CH3 H3CO TMS
O OH (COCl)2, DMF, CH2Cl2 H3CO
HO
N
Et3N, CO2CH3 O NH
OCH3 H3CO OTf
NH2.HCl H3CO
OCH3
OCH3
OCH3 (67%) TBAT, THF
OCH3 (70%)
OCH3
H3CO
LiOH, H2O N
HCl/
H3CO
(61%) OCH3
Papaverine
OCH3 J. Am. Chem. Soc. 2008, 130, 1558

Applica?on: Total Synthesis of Quinocarcin
_________________________________________________________________________
OMe OMe
O O O
OH
Bn Bn
H Me N N
N + O
N N NH
O O
OMe OMe OMe
OMe O OMe BnO
OBn
Quinocarcin
O
OMe O
1. N-Methyl morpholine Bn BnO
Bn O Cl
N MeCN, -20oC N
DMAP, Et3N
+ HN
HN N
O S 2. MaOMe, MeOH CH2Cl2
Br
O ( 74%, 2 steps) O ( 93%)
O (99% ee)
O OMe OMe
OMe O OTf O
Bn Bn
Bn TMS N
N Y(OTf)3, MeOH N OMe
O
N NH N
BnO CH2Cl2, reflux O TBAT, THF, 40oC O
OMe OMe
O O ( 69%) BnO (60%) OMe
OBn
O O
1. H2/ Pd-C, THF, rt OMe 1. HCHO, Pd(OH)2/C, H2O, MeOH (80%) OH
2. NaBH3CN, Con HCl, H 2. LiOH, THF, H2O, rt H
Bn Me
MeOH 3. Li, NH3 (l), THF -78oC to -30oC N
N
3. Toluene, 110oC then 1N HCl
N N
( 55 %, 3 steps) OMe O ( 81%, 2 steps) OMe O

OBn
Jaideep Saha @ Wipf Group J. Am. Chem. Soc. 2008, 130, 17270
Reac?on Diversity of Arynes with Amides and Related Substrates
_________________________________________________________________________
O
Me
N
CO2CH3 CO2CH3 H
N CF3 N
N
HN O Me
O O
O O
t-Bu O
Me Me NH
Indolines N N
[3+2] CF3
O
Me
O S O
N
[4+2]
R' Me
R' Me
CO2CH3 O S O
O S O
N N
HN R N
R
O
Isoquinolines
[2+2] cycloaddition-[2+2]-pericyclic ring

openning-intramolecular [4+2] cycloaddition
Ts
N

Method Development for Tandem [2+2]-‐Cycloaddi?on-‐Pericyclic-‐Ring Opening-‐N-‐Tethered IMDA
_________________________________________________________________________
__________________________________________________________
-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐
R R
OTf F N
N
R' R'
+
TMS Solvent
___________________________________________________________
Ts Ts
entry enamide amido-benzocyclobutanes yield [%] OTf
__________________________________________________________ N 1. CsF, dioxane N
+
Ns Ns TMS 2.110oC
1. N Bn N 63
Bn
Ts
Ts N
Ac N H H
Ac H
N 63
2. N Bn Bn N Ts
H 18h
( 95%)
Ts
Ts
N
3. N 95
O O O O
4. 64
N N
(dr 1:1)
iPr iPr
Org .Le(. 2009, 11, 3666

Total Synthesis of Chelidonine and Norchelidonine
_________________________________________________________________________
Ts O
Ts O
N N N
R
EtO2C
-----------------------------------------------------------------------------------
Ts
Ts N O O
N
N
R H CO2Et
R = n-pent 58% 33% 81%
R = Ph 64%
Retrosynthesis of Chelidonine:
O O O O
O O R O R O
R R
N N N N
H O
O O
H H O
O OH O
H R'
R = Me, Chelidonine
R = H , Norchelidonine
Org. Le(, 2012, 14, 2742-‐2745

Synthesis of Enamide Fragment
_________________________________________________________________________
2.0 mol% Pd(PPh3)2Cl2

2.0 equiv CbzNH2 O
5.0 mol% CuI O O O
2.0 equiv of Et3SiH Cbz
O O Et3N, 90oC O N
O TIPS H 1.3equiv of TFA H
1.3 equiv of
H
Br 81% 94% R
R
R = TIPS
20 mol% CuI O
40 mol % DMEDA Cbz O
N
2.0 equiv Cs2CO3, 80oC
10 equiv vinyl bromide
R
89%
R = TIPS TBAF, THF
R=H 95%
Org. Le(, 2012, 14, 2742-‐2745

Comple?on of the Total Synthesis
_________________________________________________________________________
O
O Cbz O
Cbz O 1. TBAF, THF, rt, 1h N
CsF, CH3CN, rt N
O OTf 2. Xylene, heat
A O O
O TMS O O
79% H
TIPS
O
O Cbz O
O BH3-THF, rt N
O Cbz O 1. Dess-Mertin Periodinane H
Cbz then H2O2/ NaOH
N N 2 NaBH4-EtOH O
H
O H
O
( 70%-2 steps) ( 70%, dr. 1:1) H ( 70% overall) O OH
O separation of O OH
cis-isomer
1. Dess-Mertin Periodinane H2, 10% Pd/C
2 EtMe2N-AlH3, THF EtOAc/ EtOH ( 1:4)
( 55%) (81%)
O
Cbz O O O
N Me O O
H
N N
H H
O O
TIPS H
A H
O OH O OH
Org. Le(, 2012, 14, 2742-‐2745

Side Reac?ons
_________________________________________________________________________
O O O
Cbz O Cbz O Cbz O
N N N
aromatization
O O O
O O O
O Cbz O
O HN O Cbz O
Cbz N
N O
O O
O
O O
O H
Org. Le(, 2012, 14, 2742-‐2745

Summary
_________________________________________________________________________
  A New reac7on manifold had been demonstrated u7lizing

[2+2] cycloaddi7on cascade coupled with IMDA reac7on.
  The aryne based methodology u7lized in the current context can be
extended further for the synthesis of other alkaloid natural products

Total Synthesis of Chelidonine and Norchelidonine Via An Enamide - Benzyne - (2+2) Cycloaddi?on Cascade

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Synthesis of Chelidonine and Norchelidonine via

Current Literature Presenta7on

J. Am. Chem. Soc. 1953, 75, 3290

Jaideep Saha @ Wipf Group

Eur. J. Org. Chem. 2008, 6053.

Bond Energy: Acetylene 76 Kcal/ mol

PNAS, 2007,104, 16793

Angew.Chem. Int. Ed. 2012, 51, 3766

Jaideep Saha @ Wipf Group

1. Synthe7c strategies involving nucleophilic addi7on onto arynes.

2. Strategies based on Inser7on reac7on.

3. Cycloaddi7on Reac7ons.

Jaideep Saha @ Wipf Group

J. Chem. Soc. C. 1971, 2712.

J. Am. Chem. Soc. 1978, 10, 6218

J. Am. Chem. Soc. 1994, 116, 9471

J. Am. Chem. Soc. 2005, 127, 5340

Jaideep Saha @ Wipf Group

( 50%) ( 69%) ( 61%)

Applica7on in the Enan7oselec7ve Synthesis of (-­‐) Curvularine

Org. Le(. 2010, 12, 1612

J. Am. Chem. Soc. 2005, 127, 13112

Electron deficient system, Electron sufficient system,

TMS Pd2 (dba)2. dppf, CsF

Org .Le(. 2008, 10, 2393

Mechanism for bis allyla?on of aryne

Jaideep Saha @ Wipf Group

OTf CH3CN, 80oC, 4h OMe

J. Am. Chem. Soc. 2001, 123, 12686

J. Am. Chem. Soc. 2008, 130, 1558

Jaideep Saha @ Wipf Group

( 55 %, 3 steps) OMe O ( 81%, 2 steps) OMe O

[2+2] cycloaddition-[2+2]-pericyclic ring

Jaideep Saha @ Wipf Group

Org .Le(. 2009, 11, 3666

Retrosynthesis of Chelidonine:

Org. Le(, 2012, 14, 2742-­‐2745

2.0 mol% Pd(PPh3)2Cl2

Org. Le(, 2012, 14, 2742-­‐2745

Org. Le(, 2012, 14, 2742-­‐2745

Org. Le(, 2012, 14, 2742-­‐2745

 A New reac7on manifold had been demonstrated u7lizing

Jaideep Saha @ Wipf Group

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1.  Synthe7c strategies involving nucleophilic addi7on onto arynes.

2.  Strategies based on Inser7on reac7on.

3.  Cycloaddi7on Reac7ons.

Applica7on in the Enan7oselec7ve Synthesis of (-‐) Curvularine

Org. Le(, 2012, 14, 2742-‐2745

Org. Le(, 2012, 14, 2742-‐2745

Org. Le(, 2012, 14, 2742-‐2745

Org. Le(, 2012, 14, 2742-‐2745

  A New reac7on manifold had been demonstrated u7lizing