2010/09/01 (Wed)Kenta Saito (M1)

Literature Seminar

Total Synthesis of (+)-Complanadine A
isolated from Lycopodium complanatum
Ref. T etrahedron Lett. 2000 41 9069
An Inducer of Neurotrophic Factor Excretion

N

3N H

2'Pseudosymmetry
HNN

H

H

Total Synthesis by Sarpong and Siegel
Ref. JACS 2010 132 5926 (Sarpong et al)
JACS 2010 132 5924 (Siegel et al)(+)-Complanadine A

Contents :1 : Synthetic Strategies by Sarpong and Siegels
2 : Ir-catalyzed C-H Boryration
3 : Cobalt-catalyzed [2+2+2] cycloaddition
4 : Sarpong's Total Synthesis
5 : Siegel's Total Synthesis
1 : Synthetic Strategiesby Sarpong and Siegel
Sarpong's Strategy

Sarpong'sStrategy

NN H

HN

N

Siegel's Strategy

Siegel'sStrategy

HH12 : Ir-Catalyzed Borylation

Miyaura , Hartwig et al JACS, 2002, 124, 390
Miyaura , Hartwig et al JACS, 2005, 127, 14263(i) Introduction
Scheme and Tris-boryl complex (X-ray)(ii) Mechanistic study : determination of catalyst system
B (V)E
possible catalyst system :Ir(V)1) Ir(III)2) Ir(I)
Ir(III)

FADC
Two possible catalystic cycles
1

H NMR spectra tracing

Isotope tracing Part 1(for determination of "key" complex)(t)Benzene-d 6 + B2pin2-d 24 (catalyzed by A)
A is unlabelled
Results :(conversion)

PhBpin-d 5 : PhBpin-d 17 = 68 : 32 (10%)
PhBpin-d 5 : PhBpin-d 17 = 47 : 53 (50%)
PhBpin-d 5 : PhBpin-d 17 = 17 : 83 (100%)
This shows ...
the reductive elimination of B2pin2 doesn't
occur.

This reaction occured directly from A orboryl complex generated from A.
2

Kinetic studyIsotope tracing Part 2

An exchange between B2pin2-d 24 and A
occurs at higher tempreture.
This exchange process is degenerate.

(for determination of "key" complex)
B2pin2-d 24 + A (absence of arene) at RT
A is unlabelled
Unlabelled B2pin2 is generated slowly ...
However,
1,2-dicholorobenzene + B2pin2-d 24 at RT(catalyzed by unlabelled A)

This shows ...
Ir(I)Ir(III) system : an exchange processdepends only reductive elimination of B2pin2
from A. The reaction would be zero-order in
added [B2pin2-d 24].

monoboryl arene is generated faster(even at below RT)

Ir(III)
Ir(V) system : The reaction would
be first-order added [B2pin2-d 24].

Isotope tracing examinations show the rate ofelimination of B2pin2 to generate a monoboryl
complex is much slower than the rate ofreaction of A with arene.

result : the rate constant for the exchange
process depended linearly on [B2pin2-d24].
This shows the exchange process occurs byreaction of B2pin2-d 24 with A.

Ir(I) isn't an intermediate.

Conclusion : This catalyst system is Ir(III)

Ir(V).

Cl(iii) Rate limiting step

Clormeasuring isotope effect

Cl+ B2pin2[Ir] = Ad4Cl( [A] = 4.0

KineticIsotope
Effect(kH/kD)

Ausing two saparate reactions of 1,2-dicholobenzene and 1,2-dicholorobenzene-d4
10-3 M , [B2pin2] = 0.315 M , [arene] = 0.284 M )result : isotope effect is 3.3 0.6Conclusion : C-H bond cleavage is turnover-limiting and is consistent with thefirst-order dependence of the catalytic reaction on the concentration of arene.
(iv) Kinetic study
Plots of ln[arene] vs time
These are linear 3-4 half lives.
using four arenes in catalytic reaciton
CF3ClClCF3

1,3-bis(trifluoromethyl)-benzene , t1/2=1h , 0 C
1,2-dicholorobenzene , t1/2=1h , 10 C
benzene , t1/2=1h , 25 C
m-xylene , t1/2=1h , 40 C

Reaction of two-different concentrationof B2pin2
containing arene (0.299 M)
B2pin2 (0.492 M and 1.38 M)
others (10 mol%)result : kobs = 1.9
kobs = 1.7

0.2
0.2

10-4s-1 (0.492 M)
10-4s-1 (1.38 M)

The reaction is zero-order in B2pin2.
first-order in arene
3The reaciton is inverse first-order in [COE].

The reaciton is first-order in [Ir].
(COE is added)
These kinetic studies show COE inhibits
the reaciton.
therefore, removing COE after catalyst
is generated would promote the reaciton.
Experimental condition :(a) B2pin2 +(b) B2pin2 +A
2 mol%Bpin

A
2 mol%

Bpin

9-BBN (20 mol%)as reductant ofCOE

The reaciton is half-order in [Ir].
(COE is abcence)

Results : (a) 15% (8h) , 25% (20h)(b) 44% (8h) , 80% (20h)Consuming the COE ligand does lead tosignificant rate enhancements.

4(v) Catalytic cycle
The reaction's catalytic cycle proposed based on these mechanistic studies below.
The reasons that complex 1 is thisreaciton's catalyst are shown below.
1) induction period is observed when
the catalyst is generated in situ from[Ir(COE)2(OMe)]2 and dtbpy, but
induction period is absent when thereactions are intiated with isolatedcomplex 1.
2) the isotope effects are similar forthe catalytic reacitons and the stoichiometric reactions of complex 1.
3) the selectivities for reactions ofB2pin2 with different arenes and heteroarenes are similar for the catalytic
reactions and the stoichiometric reactions of complex 1.

(vi) Reactivity and selectivity of substrates

However...

a) reactivity of arenea2) electronic-rich five-membered heteroarene vs electron-neutral arenea1) electronic-rich arenes vs electron-poor
arenes
The catalytic reaction occurs faster with electron-poor arenes than with electronic-richarenes. (see. (iv) Kinetic study)
The precursor to C-H bond cleavage is known
to be a 2- -complex.
The stability of theto reactivity.

2- -complexes contributes

Ref : Jones , Perutz JACS, 1993, 115, 7685b) site selectivity or regioselectivity in arene
steric effect vs -complexes stability effect
In the reaction of phenanthrene,
borylation would occur at the 9-position.
( -complexes)
borylation would occur at the 2 and 3-position.
(steric effects)
result : 2- and 3-borylated isomers are observed.

The catalyst reaction occurs faster with electron-rich heteroarenes than with arenes.
conpeting with reactions of benzene andthiophene, 2-thienyl pinacol boronate ester ismajor product.
+SA , B2pin2

S

Bpin

Five-membered 2-heteroarene complexes
are more stable than 2- arene complexes.

the steric effect on regioselectivity is stronger
than the stability of the -complexes.

M2

phenanthrene- arenecomplex

5

(vii) Regioselectivity of arene and heteroarene
Hartwig et al Chem. Rev., 2010, 110, 890

In arene, meta product is major.
In 5-membered hetaroarene, 2-borylated products are major.
However, in 6-membered heteroarene (ex. pyridine, quinoline) , 3-borylated products aremajor and 2-borylated products aren't obtained.

"T he regioselectivity of the borylation of pyridine and quinoline to give 3-borylated products
is perplexing. One possibility is that an iridium complex or a boron compound binds
reversibly to the basic nitrogen and both activates the substrate f or reaction and blocks
borylation at the 2-position."
Hartwig et al T etrahedron Lett., 2002, 43, 5649

6

3 : Cobalt-catalyzed [2+2+2] cycloaddition(i) Introduction
Omae et al Appl. Organometal.. Chem, 2007, 21, 318
Organocobalt compounds in organic synthesis have three characteristic reacitons.
A) A high affinity to C-C -bonds or C-N -bonds.
B) A high affinity to carbonyl groups.
C) Easily tending to form square-planar bipyramidal six-coordination structures at thesquare-planar position, and to bond with one or two carbon atoms at axial position.
NIcholas reaction , Pauson-Khand reaction and [2+2+2] cyclizaiton are based on character A.
(Pauson-Khand reaction is also based on character B)(ii) Nicholas reaction (character A)

The cation at the -position of the alkynes is stabilized by dicobalt hexacarbonyl acetylene
moiety.
Ref : Mayr et al JACS, 1998, 120, 900
Cobalt-alkyne complex is stable, so this is also used for protection of alkyne.
Alkyne's -bonds are used for forming cobalt-alkyne
complex. This alkyne isn't active.

7

(iii) Pauson-Khand reaction (character A , B)ex) Nicholas reaction andPauson-Khand reaction

Schreiber et al JACS, 1997, 119, 4353

The cobalt-alkyne complex same as
Nicholas reaction is revealing.
(iv) [2+2+2] cyclization
catalytic cycle

Ref : Varela , Saa et alChem. Rev. 2003, 103, 3787

Oxidative coupling of two coordinatedalkynes to afford cobaltaqcycle

CpCoL2-catalyzed pyridine synthesis

8

(iv) Steric effect vs electronic effectSaa et al JACS, 1998, 120, 12147

RR

R

CpCp(CO)2+C

toluene,NCo

R
Cp

C N

Co

aR+R
Cp

C NbRRN
RN

R

If steric effect is important...

complex b is major.
Ref : Wakatsuki et al JACS, 1983, 105, 1907

substituent B is larger than A

Path Cs-b is favorable because
the bulkier substituent B is directedto the most vacant site.

However, path Cs-c is unfavorable
because a large steric repulsion
between two bulky B at the positions.

9If electronic effect is important...

complex a is major.
Ref : Hoffmann et al JACS, 1980, 102, 2952

C2 C3HOMO
model of ethylene polarization

two ethylene and metal

LUMO

Summary,
The activation energy is dominated by C2-C3 bondformation.
The * mixing is enhanced when the large lobes ofthe polarized * face each other in the positions.

Result :electronic effect is stronger than stericeffect.

104 : Sarpong's Total Synthesis
Retro-synthesis

Synthesis of 12OO

retro-aldol
reaction

O1) PhSH , LDATHFSPh2) NH4Cl aq(+)-Pulegone
TCI : 25mL 13,500 YenO

acrylonitrile,AIBN, Bn3SnH

OmCPBAI2 , pyridine

DCM

DCM
95%I

O
CN

benzene, 70%

49% (3step)
protection

OO
CN

LAH , Et2OOO
NH290%
1211Summary1) Me chirality : using natural product2) quartenary center : Intramolecular Mannich-type reaciton3) pseudosymmetry : monomer, 3-selective C-H borylaiton
125 : Siegel's Total Synthesis
Retro-synthesis

Amidation of propargyl alcohol

Scheme1314Summary1) quartenary center : Cu-catalyzed amine substitution ofpropargyl amidation2) pseudosymmetry : Late stage Cobalt-catalyzed [2+2+2]
cyclization (regioselectivity by PPh3)

15