Literature seminar

Keita Nagawa (B4)
2008. 01. 16

Total Synthesis of (±)-Marcfortine B
π-Allylpalladium for the assembly of complex cyclic structure
O

Isolation: Penicillium roqueforti
Structural Elucidation:

HNN

J. Polonsky et. al. J. Chem. Soc., Chem. Commun. 1980, 601.

Bioactivity: Potent anthelmintic activity
Total Synthesis: B. M. Trost et. al. J. Am. Chem. Soc. 2007, 3086.
Total synthesis of related alkaloids

ONHO

Paraherquamide A, B
Stephacidine A, B
Marcfortine CO

R. M. Williams et al. J. Am. Chem. Soc. 2003, 125, 12172.
J. Am. Chem. Soc. 1996, 118, 557.
P. S. Baran et al. J. Am. Chem. Soc. 2006, 128, 8678.
R. M. Williams et al. Tetrahedron 2007, 63, 6124

Marcfortine B (1)Cotents
1. Strategy of Total Synthesis
2. π-Allylpalladium-Mediated Cycloaddition Reaction
2-1. General Methodology - [3 + 2n] Cycloaddition
2-2. Possible Mechanism
2-3. Substituents Effect of Trimethelenemethane
2-4. Recent Development of π-Allylpalladium-MediatedCycloaddition Reaction
2-5. Pd-Catalyzed Carboxylative [3 + 2] TrimethylenemethaneCycloaddition

3. Total Synthesis of (±)-Marcfortine B
4. Appendix (Total Synthesis of (±)-Marcfortine C)

1. Strategy of Total Synthesis
O
HN

RadicalO
Cyclization
HN

NS
NO
N
H

OO

Marcfortine B (1)

MeS
O

O
HN
NOO
NOMe
PMB OMe2NOMe
PMB OMe
31/10

O
Michael Addition
O
HN
MeO2C
N

H2N

O

H2N

HN+N

MeO2C

OH

6

HO2C
O
NH

O

OMe

N
H

OMe

OOMe
OMe

4Pd-Catalyzed
Carboxylative TMM
Cycloaddition

5NOMe
Boc OMe
7TMSOONOMe
Boc OMe10N
Boc OMe+ TMSOMe

OCO2Me89

Advantages of Pd-catalyzed carboxylative [3 + 2] TMM cycloaddition
Compared to other spiro-oxindole forming reactions- Oxidative rearrangement (Figure 1.), Intramolecular Heck-rxn., etc.
Construction of a heavily substituted spirocyclic cyclopentane ring at the early stage from simple compounds- Short and efficient synthetic route- Easy to establish the remaining stereogenic center by using the asymmetry of spirocycle
Introduction of the requisite carboxylic acid functionality at the same time
Figure 1. Stereoselective oxidation/pinacol rearrangement for another method
to construct spiro-oxindole moiety (Total synthesis of Marcfortine C)

R. M. Williams et al. Tetrahedron 2007, 63, 6124
(cf. Appendix)

2/10

2. π-Allylpalladium-Mediated Cycloaddition Reaction
2-1. General Methodology - [3 + 2n] Cycloaddition[3 + 2] cycloaddition (n = 1)O

Pd(PPh3)4(10 mol %)TMS+OAc

O

B. M. Trost et al. J. Am. Chem. Soc. 1983, 105, 2315.
B. M. Trost et al. J. Am. Chem. Soc. 1985, 107, 721.

toluene, 110 °C[3 + 4] cycloaddition (n = 2)
CO2Me
TMSPd(OAc)2 (5 mol %)Ligand (6 mol %)

+OAc

MeO2C

benzene, 45 °C

B. M. Trost et al. J. Am. Chem. Soc. 1987, 109, 3483.

Ligand = N,N'-dibenzylideneethylenediamine[3 + 6] cycloaddition (n = 3)

TMS+OAc

OPd(OAc)2 (2.5 mol %)P(Oi-Pr)3 (22 mol %)B. M. Trost et al. J. Am. Chem. Soc. 1987, 109, 615.

Otoluene, 85 °C

2-2. Possible Mechanism
Concerted mechanism or stepwise mechanism ? (Scheme 1.)
Figure 1. Proposed mechanism(for stepwise process)stepwise process
Scheme 1.

TMS

L2Pd0OAc

1E

5PdLL

PdTMS

E4LL

3
concerted process

26LL
PdE3E

Stepwise Mechanism- Alkene activation by electron-withdrawing group is necessary.
- No stereospecificity is observed with some substrates.
XY- Some reactions do exhibit near or complete stereospecificity.
- For certain substrates, several evidences were shown that
support for concerted mechanism.
(D. A. Singleton et al. J. Am. Chem. Soc. 1999, 121, 9313.)

Y+Concerted MechanismXtrans alkenes
LPdYL+

thermodynamicallystablethe trans adduct
XXYYX

cis alkenes

mixtures ofcis and trans adducts

Diastereomeric ratio from cis alkene and trans alkene
is not completely same.

For now, there is no explanation that can definitively
say which process is the most plausible.
(It depends on reaction type and substrates.)

Even if stepwise mechanism is operative, life time of 5 (inScheme 1.) is not so long for the bond rotation.

3/10

2-3. Substituents Effect of Trimethylenemethanes
Various kinds of substituents are possible, and all reactions afford the same regioselectivity.
B. M. Trost et al. J. Am. Chem. Soc. 1985, 107, 721.
Scheme 1.
R

EWG

RTMS

LNC

O

R

R

OAc

PhPdL

L

MePd

L

AcO

OAc

OAc

OAc

OAc

OAc

OAc

TMS

TMS

TMS

TMS

TMS

TMS

EWG

This intermediate is more stable- indicated by the MO calculations(B. M. Trost et al. JACS 1981, 103, 5974.)
Even vinyl, methyl and acetyl substituentsgave same regioselectivity !

For methyl substituent, two different precursors (1 and 2) produce the most stable TMM complex (3b) selectively.
Scheme 2.
B. M. Trost et al. J. Am. Chem. Soc. 1981, 103, 5972.
MeOAc

Pd(PPh3)4TMS

L
L Pd

EWG

LL Pd

Me5aPd(PPh3)4L
L Pd

5bEquilibrium of 3a and 3b is faster than cycloaddition.
The intermediate 3b is more stable than 3a.

fastOAc

Me4a1

EWG+EWG

slow

3a

MeEWG

MeL
L Pd

EWG

EWG
EWG

TMS

slow

MeMe24b3bmajor product

MeMe5c2-4. Recent Development of π-Allylpalladium-Mediated Cycloaddition Reaction(1) Pd-Catalyzed [3 + 3] Cycloaddition of Trimethylenemethane with Azomethine Imines

OAcTMS
1 (2.0eq)+N

T. Hayashi et al. J. Am. Chem. Soc. 2006, 128, 6330.

OON

Ph
H
2a (1.0eq)

Pd(PPh3)4(8 mol %)CH2Cl2, 40 °C

ONN

N

Ph
3aR

N
H

1-Alkylidene-3-oxopyrazolidin-1-ium-2-ides- Isolable and stable azomethine imines- Derived from pyrazolidin-3-ones and aldehydes- 1,3-Dipoles in the context of [3 + 3] cycloadditions

The effect of substituents on TMM precursor
Scope of azomethine imineTable 2.

Scheme 2.

high yield(aryl, heteroaryl,alkenyl)

Scheme 1.
less effective(alkyl)

Cycloaddition step is faster than equilibrium between 6 and 7(striking contrast to [3 + 2] cycloaddition Trost reported - cf. 2-3.)high diastereoselectivity

4/10

(2) Synthesis of Spiro[2.4]heptanes via π-Allylpalladium Intermediate (Extension of Pd-Catalyzed [4 + 2] Cycloaddition)
T. Hayashi et al. J. Am. Chem. Soc. 2007, 129, 14866.
γ-Methylidene-δ-valerolactones- Generating 1,4-zwitterionic speciesOOPdCO2MeArImportant effect of phosphine ligand

Pd- Derived easily from known compounds
OTBSOMs

O

CO2Me

1. NaH, THF

CO2Me

2. TBAF, THF+ PhO
Ph

y. 66 %

CO2Me3O

EWG

O+PdCp(η -C3H5)(5 mol %)P(Oi-Pr)3 (10 mol %)

CO2Me

Ar

CH2Cl240 °C, 24 h

21

EWG

Ar CO2Me

3

Proposed catalytic cycle
OO
PdAr

palladacyclobutane

binap
dppf
L=P(OMe)3P(Oi-Pr)3
small and bidentate

CO2MePdO

Pd(ππ-allyl)L2 spieces

cyclopropanation

OAr

CO2MePd(ππ-allyl)L spieces(t-Bu)2P

1,4-zwitterionic spieces
L=P(o-Tol)3
bulky monodentate

6-membered ring closure(3) Pd-Catalyzed Asymmetric [3 + 2] Trimethylenemethane Cycloaddition
5 mol % Pd(dba)2
10 mol % Ligand

OTMS

OAc +(1.6 equiv)

B. M. Trost et al. J. Am. Chem. Soc. 2006, 128, 13328
Table 2. Reaction with aryl- and alkylidene tetralones

OMe toluene, 23 °C

PhPh(1.0 equiv)

OMeOO
P NO

L2-(R,R,R)
y. 78 %ee. 29 %L3-(rac,R,R)
y. 77 %
ee. 44 %OP NOL6-(S,S,S)y. 80 %
ee. 58 %Table 1. Substrate scope

ester

cycloalkyl OK(but 6-memberedring is not effective)ee. 62 %(by cooling the rxn.)

Proposed mechanism

ee. 73 - 84 %at -25 °C
ketoneelectron-rich or electron-pooraromatic enones- ee slightly decreased
nitrilemodest ee.

Enantiodetermining step
Difficulty: Large distance between chiral ligands
and the asymmetric bond-forming point

5/10

(4) Pd-Catalyzed Asymmetric [4 + 3] Cycloaddition with Nitrones
T. Hayashi et al. J. Am. Chem. Soc. 2007, 129, 12356.

Improving ee
by changing N-substituents

Proposed catalytic cycle

1,3-Dipoles

Another possibility - azomethine imine

1,4-zwitterionicspieces

2-5. Pd-Catalyzed Carboxylative Trimethylenemethane [3 + 2] Cycloaddition
B. M. Trost et al. J. Am. Chem. Soc. 1986, 108, 6051.

Background concept

The initial Pd-TMM spieces

The second Pd-TMM spieces

TMS

E

TMS
TMS

TMS

E
EWG

E

OCOR
L

Pd

Path ALLPdLL

PdEL

EWG

Path B

Utilizing the silyl-substituted
Pd-TMM precursor as
dual-purpose conjunctive reagent

EWG

Intercepted by a reactive electrophile (Path A)
before normal cycloaddition step proceeds (Path B)

TMS
EWG

Using methyl carbonate
as leaving group

Scheme 1.

OCO2MeMe3SiPd(0)

Me3Si

SiMe3

OCO2Me
SiMe3

PdPd
Me3Si

OCO2MeConvenient carrier of CO2

SiMe3
Me3SiOCO2Me

The second Pd-TMM spieces

Carboxylic acid may be trapped astrimethylsilyl ester.

O

Me3Si OMeO

Me3SiO

Me3SiO
Pd

Me3Si
OMe

EWG

Desilylation of the silyl ester occurs
during column chromatography.

EWG

PdO- Pd(0)EWG

The initial Pd-TMM spieces

Pd

Me3Si

Me3SiO

Me3SiOMe + CO2OOPdOPd
Me3Si

silicagelcolumn chromatography

Me3SiO
EWG

HO2C
EWG

6/10

3. Total Synthesis of (±)-Marcfortine B
TMS

Pd-Catalyzed
Carboxylative TMM
Cycloaddition
RO2CTMS

8 OCO2Me1) acetone, HCl, rt
70 %ONHOMeNOMe
Boc OMe92) Boc2O, DMAP,NEt3, CH2Cl2, 85 %OMePd(OAc)2, P(OiPr)3,O

10Preparation of 6N

HBr

100 bar H2, cat. Rh/Al2O3,aq HBr pH 3

CONH2HN65 °C, quant.

OHO

toluene, reflux

NOMe
Boc OMeCONH2

H2NOCOHOHNMeO2C1) mCPBA, CH2Cl2, 0 °C,89 %1) MsCl, NEt3, CH2Cl2, 0 °C

2) DBU, THF, 0 °C to rt,72 %O2) 6, NEt3, DMSO, rt

O

NOMe
Boc OMeNOMe
Boc OMe
13O12O

H2N

MsCl, NEt3, CH2Cl2, 0 °C

11 (R = Me)

OH
66'
MeO2C

7 (R = H)

Me2SO4, K2CO3,acetone, reflux,
93 % (2 steps)

Extremely mild reagent
for Boc deprotection(Chem. Commun. 1996, 2509.)

N

MeO2C

EtOAc, rt,89 %

O

N

MeO2C

SnCl4

then DBU, 84 % (3 steps)

H2N

N
OMe
Boc OMeON
H

14OMeOMe
5Michael Addition
Internal protonationby the upside amide hydrogen

O

H 2N

ON

MeO2C

THF, 0 °C to rt

MeO2C

O

O

HNNO
N
HOMe

5ON

MeO

KHMDS

N
H

O
HNOMe

NH

OMe
OMe

15OMeOMe

4

What if N-methylated congener ?
O
NO
NH2Me O
N

MeO2C

N

MeO

MeO2C

ONHOMeOMe

NOOO

HNNH

Efficient shielding of
the re-face of the Michael-acceptor
by the aromatic portion of the molecule

OMe
OMe

NComplete inversion Hof stereoselectivity

OMe
OMe

7/10

O

H2NO
MeO2C

N

MeO2C

O

HN

MeO2C

NN
HN

PMBCl, Bu4NI, K2CO3

KHMDS
THF, 0 °C to rt,quant.

O

HN

acetone, reflux,
95 %

O
N
H

OMe
OMe

OMe

ONOMe
PMB OMe

OMe
4516O

S

HN

HON

HN

O

KHMDS, THF, CS2,-78 °C to rt

DIBAL
CH2Cl2, 0 °C,86 %

O

MeS

N

then MeI, 75%OONOMePMB OMeNOMe
PMB OMe317

Radical Cyclization
OSMeSOOHNHNNNAIBN, Bu3SnH?

benzene, refluxOONOMePMB OMeNOMe
PMB OMe

318OHN

3Bu3SnHN

Superstoichiometric amounts of AIBN and catalytic
amounts of Bu3SnH were necessary for optimum
yields of 2.

ONO
HN

The expected saturated product 18 was not obtained.
Instead, alkene 2 was the sole isolable product.
- Attack of the secondary alkyl radical 19 on the AIBN
rather than reacting with Bu3SnHOMePMB OMe18NNCONOMePMB OMeCNCNOHNAIBNN- N2 ,CNO

N H
HNNC
1,4-hydrogenabstraction

NO
HN

NHN

CNN

HN N

N

19OON

O
N

OMe

CNN

OMe

PMB OMePMB OMe

2021OMePMB OMe

28/10

OS
MeS
O

O

HN

HN
N

170 mol % AIBN,
20 mol % Bu3SnH

HN

50 bar H2,
Crabtree's catalyst(15 mol %)NN

CH2Cl2, 89%

benzene, reflux,
61 %

O

O

ON
OMe
PMB OMe3O
NOMe
PMB OMe2NROMe18 (R = PMB)

TFA, anisole,
reflux,91 %Crabtree's catalyst

OMe

22 (R = H)

PCy3Ir
NPF6O
HNO
HNN1) BBr3,CH2Cl2, 0 °C
2) prenylbromide, KI, Cs2CO3,acetone/H2O 10/1,62 % (2 steps)

N1) mCPBA, CHCl3, 0 °C to rt,then aq NaHSO3O
N
HOHO232) SnCl4, dioxane, rt3) MeP(OPh)3I, DMPU, rt,
42 % (3 steps)

O
N
HO
O

Marcfortine B (1)9/10

4. Appendix (Total Synthesis of (±)-Marcfortine C)
R. M. Williams et al. Tetrahedron Lett. 2007, 63, 6124.;
R. M. Williams et al. Angew. Chem., Int. Ed. 2007, 46, 2257.
A. W. Grubbs et al. Tetrahedron Lett. 2005, 46, 9013.;
R. M. Williams et al. Tetrahedron Lett. 2002, 43, 2149.;

Retrosynthetic Analysis

141420

20

19

14

20

19

CH2O, Me2NH, AcOH
rt, 85 %1915

15

Marcfortine C(3)10/10