January 17, 2012
Seiko KITAHARA (B4)

Literature Seminar (B4 part)

Total synthesis of Laulimalide
O

H
23

OH

O

20

17

O

O
1

15

OH
H

3

5

O

H
9

1: Laulimalide(fijianolide B)

Contents
1. Introduction
2. Previous Total Synthesis
2-1. Retrosynthetic Analysis
3. Trost's Total Synthesis-toward the atom economy3-1. What is "synthetic efficiency" ??
3-2. Retrosynthetic Analysis
Marine Sponge,
3-3. Total Synthesis
Cacospongia mycof ijiensis
3-4. Asymmetric Direct Aldol Reaction
via a Dinuclear Zn Catalyst
3-5. Rh-Catalyzed Cycloisomerization
3-6. Ru-Catalyzed Alkene-Alkyne Coupling

Barry M. Trost1. Introduction
O

H
23

OH
O
20

H
15

O

O
1

3

5

O

17

20

OH
H

H
9

On exposure to acidO

(fijianolide B)

15

O
H

(within two hours)

1: Laulimalide : intrinsically unstable

OH

O

O

17

OH

isolaulimalide(fijianolide A)<Isolation>-Fromvarious marine sponges such as hyattela sp., Cacospongia mycof ijiensis, f asciospongia rimosaa marine sponge in the genus Dactylospongia
a nudibranch, Chromodoris lochiwith its tetrahydrofuran containing isomer isolaulimalide<Structure>-Determined NMR analysis and X-ray crystallographic analysis
Corley, D. G et al. J. Org. Chem. 1988, 53, 3644.
Quinoa, E et al. J. Org. Chem. 1988, 53, 3642.
-20-membered macrolide<Biological activity>-like Taxol (paclitaxel), induces microtubule polymerization and stabilization-unlike Taxol (paclitaxel), retains activity in multidrug resistant cell lines-binds to a different site than other known microtubule stabilzers
suggesting new opportunities forchemotherapy ??

<Total synthesis>-Hot topic for over a decade (more than 10 reports !)due to its significant clinical potential
its strict natural supply
unique and complex molecular architecture
Ghosh, A. K. et al. J. Am. Chem. Soc. 2000, 122, 11027.
Ghosh, A. K. et al. J. Org. Chem. 2001, 66, 8973.
Mulzer, J. et al. Angew. Chem., Int. Ed. 2001, 40, 3842.
Paterson, I. et al. Org. Lett. 2001, 3, 3149.
Enev, V. S. et al. J. Am. Chem. Soc. 2001, 123, 10764.
Wender, P. A. et al. J. Am. Chem. Soc. 2002, 124, 4956.
Crimmins, M. T. et al. J. Am. Chem. Soc. 2002, 124, 5958.
Williams, D. R. et al. Tetrahedron Lett. 2002, 43, 4841.
Nelson, S. G. et al. J. Am. Chem. Soc. 2002, 124, 13654.
Ahmed, A. et al. J. Org. Chem. 2003, 68, 3026.
Gallagher, B. M. et al. Med. Chem. Lett. 2004, 14, 475.
Uenishi, J. et al. Angew. Chem., Int. Ed. 2005, 44, 2756.
Gollner, A. et al. Chem.-Eur. J. 2009, 15, 5979.
Trost, B. M. et al. J. Am. Chem. Soc. 2009, 131, 17089.

OH

2. Previous Total Synthesis
2-1. Retrosynthetic Analysis

O

H
23

OH

O

20

17

O

O
1

15

O

Route0

5

O

23

15

20

17

O

O
1

H

Route2
Macrocyclization
by Yamaguchi lactonaization

9

Route1
Macrocyclization
by Still-Gennari reaction

1: laulimalide

Fragment union
by allyl transfer

OH Route4 Route3

H

OH
H

3

Fragment union
by Julia-Kocienski olefination

asymmetricepoxidation

OH
H

3

O

5

H
9

2

Although more than 10 syntheses were reported, the retrosynthetic route was limited.
(route0the combination of route1-4)

3. Trost's Total Synthesis
3-1. What is "synthetic efficiency"??

Trost, B. M. et al. Science. 1991. 254, 1471.

Efficienct synthetic methods require to
chemo-/regio-/diastereo-/enantio-selectivity
atom economy = how much of the reactatns end up in the productAn process that is both selective ant atom economical remains a challenge.
Transition metal catalysis enable this ??

Cycloisomerizations offer opportunities for enhancing efficiency
for construction of difficult medium and large rings
a unsaturation

converted toa ring unsaturation(with only a hydrogen shift)

Trost used 3 atom economic reactions in total synthesis of laulimalide, and 2 of these is cycloisomerization

1. synthesis of syn-diol
Zn-cat.

2. synthesis of dihydropyran

3. synthesis of 1.4-diolHRu-cat.

3-2. Retrosynthetic Analysis
Trost's retrosynthetic anlysis is based on the notion that laulimalide 1 could be formed from 1,4-diene 3.

Oasymmetricepoxidation

OH

H

O
20

23

O

15

15
20

23

17

O

OPMB

H

OH

O
1

H

O

5

3

17

O

OH

O
1

H

H

9

H

O

5

3

9

2

1: laulimalide
allylictransposition

O

OPMB

H

O

17

20

23

OPMB

H

OH
O

O
1

Still-Gennar iolef ination

5

3

OH
O

O
H

O

1

H

H

9

O

PMP

O

17

20

O

15

O

OMOM

N N
N
N
S
23
O
O Ph

O

H

H

17

20

+
O

15

O

OMOM

1

O

9

3

4

OPMB

23

H

O

5

3

Julia-Kocienski
olef ination
H

15

17

20

23

15

Ru-catalyzed
alkene-alkyne
coupling

5

P

6

7

F3CH2CO OCH2CF3
+

H
H

3

O

5

H

O

H

HO

9

9

9

O
8

OBn
9

OBn
10

3-3. Total Synthesis

Trost, B. M. et al. J. Am. Chem. Soc. 2009, 131, 17087.

<Synthesis of 6>
O

OH

Cl

N N
N
S N
Ph
12

HO

2) CuI, propenylmagnesium bromide,
THF (99%)

11

MesN
Cl

1) DEAD, PPh3,1-phenyl-1H-tetrazole-5-thiol (82%)

NMes
O

H

Ru
PCy3Ph

N N
N
N
S
O
O Ph
6

Et2Zn, 10 mol% Pd(OAc)2,
25 mol% PPh3, allyl acetate,
THF (62%, 76%brsm)

1) 15 mol% Mo7O24(NH4)6 4H2O,
H2O2, EtOH (83%)

N N
N
N
S
Ph

O
13

2) 3 mol% G2, CH2Cl2(0.015 M) (95%)

G2<Synthesis of 5>SOS1) H2C=CHMgBr, CuI,THF (95%)2) MOMCl, i-Pr2EtN,
CH2Cl2 (97%)

OH

H
O

14

+

OMOM

3) MeI, CaCO3,
9:1 MeCN/H2O (85%)

N
Et

15

O
16

15 mol% (R,R)-I,
THF (53%, 10:1 dr)

Et

Ph
Ph

O
Zn

PMP
1) p-MeOPhCH(OMe)2,
10-CSA, CH2Cl2 (81%)2) NaBH4, THF (86%)

O
H
O

O

OMOM

7

3) Dess-Martin periodinate,
CH2Cl2

N

OH

Zn
O

N
Et

O

OH OMOM
Me17(R,R)-I

1) 6, LiHMDS, 3:1 DMF/HMPA 64% (64% over 2 steps)2) DIBAL-H, CH2Cl2 (61%)

O

OPMB

H

OH OMOM
18

O

OPMB

H

(CF3CH2O)2P(O)CH2CO2H,
2,4,6-trichlorobenzenoylchloride,i-Pr2EtN, THF,

O

then DMAP, PhH (99%)

O
5P
F3CH2CO OCH2CF3

O

O

OMOM

N

Ph
Ph

12

13: Pd-catalyzed allylic etherification using Zn(II) alkoxides

Kim, H. et al. Org. Lett. 2002, 4, 4369.

-Generally, WIlliamson ether synthesis (SN2 type O-alkylation) is impractical.
R X+

DMF
SN2

R'O Na

E2

R

O

R'
Due to the strong basicity of Nu

Other products-Also in this case, allylation under basic or acidic condition were ineffective.
HO

N N
N
S N
Ph
12

base

O

N N
N
S N
Ph

Alternative approach: Pd-catalyzed allylic etherification

O

-SR

??

The addition of O-nucleophile
to an 3-allylmetal intermediate

Mild & Stereoselective

MISMATCH !

Soft

modulating the apparent "hardness" of RO=

Hard ROaliphatic alcohols:
poor nucleophilicity
R' strong hardness

Can the Zinc effect lead to "softening" ??
Zn(II)-bound alkoxides possess weakened basicity
while reatining sufficient nucleophilicity !!

-allylpalladium

the zinc effect in biochemistry: the Zn enzyme LADH

II
Zn-containing
liver alcohol dehydogenases (LADH)

LADH catalyze the hydride transferfrom alcohol to NAD. +deprotonation

hydridetransf er

Kimura, E. et al. J. Am. Chem. Soc. 1992, 114, 10134.
Parkin, G. et al. Chem. Commun. 2000, 1971.

The pKa of alcohols(normally ~16)
can be reduced by about 9 units
upon coordination to ZnII ??

Nucleophilicity is reatined.

13

6: oxidation of the sulfide into the corresponding sulfone using H2O2 and Mo(VI)catalyst-Altough sulfoxides and sulfones are important in synthetic oranic chemistry,
only a few reports are available for selective oxidation of sulfides to sulfoxides and sulfones
Kaczorowska, K. et al. Tetrahedron. 2005, 61, 8315.

The oxidation of sulfides to sulfoxides with H2O2
Several disadvantages of sulfide oxidation:
long reaction times
inconvenient reaction conditions
expensive oxidants
undesired reactions at other FGs
low yield

H2O2 is the most attractive oxidant :selectivesulfide oxidation
relative mild conditions
an ideal waste-avoiding oxidant: water is only byproduct !
only a small excess of H2O2high yieldliquid-phase reactions
good solubility in water and many organic solvents
Moreover,aqueous H2O2 has further advantages:
safty in storage, operation, and transportioncommercially available
reatively cheap

However, H2O2 alone has possibility of an over-oxidation reaction.
The oxidation of sulfides to sulfoxides with H2O2 & catalyst
Controlled oxidation of sulfides to sulfoxides and sulfones
is possible !
Chiral oxidation
Mo(VI) catalyst/H2O2 system at room temperature Jeyakumar, K. et al. T etrahedron. Lett. 2006, 47, 4573.
Jeyakumar, K. et al. Catalysis. communications. 2009, 10, 1948.
MoO2Cl2/H2O2 system

New systemused in this timeR(NH4)6Mo7O24 4H2O isR

commercially available
cheap
air stable

Substrate Scope of (NH4)6Mo7O24 4H2O/H2O2 System-Both systems provide excellent yield with short time.
-In both systems, various sensitive functional groups are tolerated
such as alkyl, allyl, vinyl, propargyl, alcohol, ketone, ester,and remarkably oxime !

<Synthesis of 10>
CO2Me

O

methylpropilate,n-BuLi, BF3 Et2O,

O

Pd(OH)2, H2,
EtOAc (97%)

O

O
O

HO

THF (93%)

OBn

CuI, MeLi, THF,
then AcOH, PhH (94%)

OBn
OBn 20

19

OH
21

22

DIBAL-H,CH2Cl2,
then Dowex 50W 8a),
MeOH (99%)

HO

MeO
AcOH, H2SO4,
H2O (82%)O

MeO

1) TEMPO, NaOCl,
KBr, NaCO3,
CH2Cl2/H2O (97%)

O

OBn

OBn

25

24

O

2) ethynylmagnesium bromide,
THF (77%)3) NaH, BnBr, DMF (96%)

OH
23

dimethyl-1-diazo-2oxopropylphosphonate,
K2CO3, MeOH (57%, 69% brsm)a)

Dowex:-One of the more common ion-exchange resins.
-A copolymer of styrene and 4-12% divinylbenzene
which has been sulfonatedto produce a strong-acid cation exchanger

HO

OBn
10

preparation of 19
O
HO

NH2
OH

O
D-aspartic acid

NaNO2, KBr,
H2SO4, -5 C, 2 h

O

Br
OH

HO

BF3, THF,
0 C to rt, 5 h

Br
OH

HO

O
1) NaH, THF, -10 C, 0.5 h2) BnBr, TBAI -10 C to rt, 1 h
O
BnO
19

<Synthesis of 8>
5 mol% [Rh(COD)Cl]2,
10 mol% [m-F(C6H4)]2PCH2CH2P[m-F(C6H4)]2,
DMF (55%)

HO

O

H

CH2=CHOTBS,
Montmorillonite K-10,
CH2Cl2 (82%)
H

H

O

H

O
OBn

OBn
9

10

8

<Synthesis of 3: Intramolecular Ru-Catalyzed Alkene-Alkyne Coupling>
5, KHMDS, 18-crown-6,
THF (E/Z = 1:5, 62%, 50% (isolated Z isomer))
H

H

O

O

H

H

OPMB

O

O

OMOM
O
H

O

H

4

8
5 mol% [CpRu(CH3CN)3]PF6,
acetone (0.001M),
50 C, 15min (99%)

O
PPTS,
t-BuOH (66%)

H

OPMB

26 R=MOM
O
3 R=H

OR
O
H

O

H

<Two failures in the step 31>

1. 1,3-allylc transposition using [2,3]-sigmatropic shift
O

H

OPMB

O

under Mitsunobu-type condition(Grieco elimination)

O

H

OH
O

OPMB

SeAr
O

O
H

O

H

H

O

H

3
1,3-allylic transposition ??

O

Hoxidation

OPMB
intramolecular[2,3]-sigmatropic shift
O

O

H

OH
O

OPMB

O
H

O

ArSe
OO
H

H

O

H

2

1. Payne rearrangement under basic condition
O

H

OPMB

O

diastereoselective
epoxidation

OH
O

O

H

OPMB

O
H

O

O
OH
O

H

H

3

O

H

28

Payne rearr.

O

H

OPMB

O
O

OH O
O

H

OPMB

O
H

corresponding
ring-contracted lactone

O

H

O

O

OH
H

27

O

H

<Synthesis of laulimalide and its analogue>
O

H

OPMB

O

O3ReOSiPh3,
Et2O, 5min (78%, 97% brsm)

OH
O
H

O

O

H

O

H

OPMB

O

H

1) Dess-Martin periodinane,
CH2Cl22) (R)-Me-CBS, BH3 THF,
THF (93% over 2 steps)
3) (+)-DET, Ti(i-PrO)4, TBHP,
4 Å MS, CH2Cl2 (88%)

O

O

H

OPMB

OH
O

O
H

O

O

O

H

OH
H

28 R=PMB

27 R=PMB

29 R=Hlaulimalide analogue

1

DDQ,
CH2Cl2/pH 7 buffer/t-BuOH
(71%)

3

O

2

(+)-DET, Ti(i-PrO)4, TBHP,
4 Å MS, CH2Cl2 (86%)

H

OH
O

H

3

O

OPMB

O

H

R=H
laulimalide

DDQ,
CH2Cl2/pH 7 buffer/t-BuOH(89%)

2: 1,3-allylic transposition utilizing Re oxo catalysis=

more active

Proposed mechanism

These catalyst are very sensitive to presence of water.
Me3Si
SiMe3 + H2O
2 Me3SiO
OH
form
inhibitthe catalytic process
O OH
Re
O O
According to kinetic study,

Some calculations confirm the involvement ofa cyclic transition state.
rds=
intramolecularrearrangement3-4. Asymmetric Direct Aldol Reaction via a Dinuclear Zinc Catalyst<A Dinuclear Zinc Catalyst Design>

Trost, B. M. et al. J. Am. Chem. Soc. 2000. 122, 12003.
Trost, B. M. et al. J. Am. Chem. Soc. 2001. 123, 3367.

two nitrogens
The strong coordinating elements for some metals
a semi-crown compound4 steps
OH

High binding affinity vs. Catalysis
Too high binding affinity inhibit
an exchange of products for others.

a phenoxide moiety(as a base)
1.The alkoxide generated in the aldol reaction
would be rapidly protonated by this.
2.The phenoxide might still be adequate
to form the enolate.

a semi-crown design meetsboth requirement:-good chiral recognition-turnover at reasonable rates

Me<Substrate scope and Proposed cataltic cycle>-hydroxyketones as donors

c.f. simple ketones as donors

simple ketone
the enolate apporaches
to the re face-hydroxyketone
to the si face-hydroxyketone
serves as a bidentate ligand.

3-5. Rh(I)-Catalyzed Cycloisomerizationof Homo- and Bis-homopropargylic Alcohols<Ru-Catalyzed Reconstitutive Condensation of Allylic Alcohols and Terminal Alkynes>
Trost, B. M. et al. J. Am. Chem. Soc. 1992, 114, 5579.

A??

The close examination of the mechanism-Ligand subsitution-Kinetic and deuterium experiments-Identity of the reactive profile

C
B

A. Vinylidene Formation
Deutrium labeling-alkyne complex

stoichiometric condition

1,2-hydrid
migration

catalytic condition
C-H insertion& deprotonation-acetylide complex(1) the NMR spectrum of 2 in CDO3D containing of NDPF4
the absense of the vinylic hydrogen&the disappearance of 13C signal for the vinylidene carbon(with all the other 13C siganls remaining)(2) deutrium loss of 3 in eq 6
reversibility of vinylidene formation(3) litte deutrium loss of 3 in eq7-protonation of -acetylide > reversal to -alkyne complex
fastersummary:-Vinylidene complex is formed.
-The equiliration of the vinylidene complex with starting alkyne is more slow then its further reaction.
B. Addition of Allylic Alcohols(1) the extremely facile loss of PPh3 from cat.1(2) addition of PPh3
retardation or the rate of the condensation reaction
addition of PPh3
within 1 h

under identical conditions except the addition
excess PPh3
(1eq. /Ru)4h(3) comparison of the reactivity of 3-buten-2-ol 5 with other alcohols
5, starically equivalent to IPA, reacted much mroe rapidly than MaOH.
MeOH

EtOH, IPANO addition (for steric reasons)precoordination of the olefinic group of 5(4) placing Me directly on the double bond of the allylic alcohols
OH

or

OH

condensation products

steric inhibition of olefin coordination(5) replacing PPh3 with the chelating ligands dppe and dppb
inhibition of the condensation reaction
preclusion of preccordination of the olefinic group of the allylic alcohols(due to relactance of the ligands to dissociate a phosphine)

P

dppe

P

dppb

summary:-Precoordination of the olefinic goup is required and actually takes place.
C. The Nature of the Allyl Intermediate : evidence regarding the role of - vs. -allyl complexes(0) precedents of Ru-catalyzed coupling
intrinsic preference for C-C bond formation to the more substituted allyl terminus
Tsuji, Y. et al. J. Organomet. Chem. 1989, 369, C51.

(1) regiochemical outcome from eq 12
retaining the positional identity of the allylic alcohola) Slower C-C bond rotation than reductive elimination
slowerfasterfaster-coordination
enhance the barrier
to rotation ... ??

(2) geometrical outcome from eq 13
retaining olefin geometry

NOT reasnableb) Slower

3

to

1

allyl slippage than reductive elimination

slowerlittle intervention of -complex(See the right column.)

scramble the olefin geometry

summary:-Judging from almost no scramble of both regimochemistry and olefin geometry,3- -allyl complex undergos reductive elimination much faster than borh allyl rotation and

3

to

1

allyl slippage .

This scheme accommodates all of the preceding observations.
If R=H (unsubstituted allyl alcohol),
D should be sufficiently destabilized
to ensure rapid reductive elimination
faster thanallyl rotation(Due to the presence of the acyl groupon an already electron-poor Ru(IV) species)
relatively slow

3

to

1

allyl slippage

But if R H(substituted allyl alcohol),the competition between the rate
for reductive elimination and 3 tois changed ! (See below.)1allyl slippage

A dramatic difference with a substituted allylic alcohol
The high regioselectivity&
The loss of olefin geometry-complex E as an obligatory intermediate or a species in dynamic equilibrium-Scrambling of olefin geometry-The high regioselectivity
reminiscent of eq11 (the reaction of monosubstituted allyl organomethallics
at the more substituted allyl terminus)
Why C-C bond formation the more substituted allyl terminus is favored ??
Precedents: 6-membered transition state

Trost, B. M. et al. J. Am. Chem. Soc. 2002, 124, 2528.
Like such a reaction, the metal itself prefers the less substituted allyl terminus
and cyclic transition state invokes allyl inversion ??

<Ru-Catalyzed Oxidative Cyclization vs Cycleisomerizationof Bis-homopropargylic Alcohols>
Trost, B. M. et al. J. Am. Chem. Soc. 2002, 124, 2528.

Mechanistic Rationale

If it iselectron richenoughIf it islesselectron rich

3 = (C4H9)4NPH6, 4 = N-hydroxysuccinimide<Rh-Catalyzed Cycloisomerization of Homo- and Bis-homopropargylic Alcohols>
Trost, B. M. et al. J. Am. Chem. Soc. 2003, 125, 7482.

3-6. Ru-Catalyzed Alkene-Alkyne Coupling
To maximize the atom economy ...

A+B

C+D

A+B

C+

Trost, B. M. et al. J. Am. Chem. Soc. 1995. 117, 615.
Trost, B. M. et al. Chem. Rev. 2001. 101, 2067.

D

a waste productDiels-Alder type reactions are ideal: They incorporate all of the atoms of the reactants
Ideal catalysis of the Alder en reaction

Alternative catalytic concept-the simplest form
-catalysis : only TS energy-one-step process-catalysis : precoordination of two reactant partners-one or more steps<Cross coupling of alkynes with alkenes>cat.

"branched""linear"the same as the above

Extremely high chemoselectivity & control of olefin geometry
free OH, TBS ehters, ketones, and esters
in either the alkene or alkyne
Generally, the major produt is the branched one.
Branching at propargylic position has significant effecton regio selectivity. (the linear product )Replacing an alkyl branch by an oxygen inverts the regioselectivity.
= the more reactive cationic complex

As the size of R3

then the linear<Proposed catalytic cycle>
This model may explain the effectof a propargylic oxygen substituent .

Ru coordinates the oxygen.

If the alkyne coordinateswith the opposite orientation ...
(possible in principle)
Syn- -hydrogen elimination of Hb

Electronic effect vs. Steric effectElectronically, 35 is favored.
Carbametalations normally prefer to attach
the less substitued terminus of the alkyne.

Which effect isdominant ??

Normally,electronic rather than steric effects
dominate leading via 35 to the branched 39.
On the other hand, as R increases in size,
steric effects bacome more important:
17
19 should be disfavored relative to 16

Sterically, 36 is favored.
When -hydrogen elimination is inhibited ...
Normally,electronic rather than steric effects
35 to thedominate liading
branched 39.
viaviaanother
process
On the other hand, as R increases in size,
steric effects bacome more important:
17
19 should be disfavored relative to 16-hydr oxy
elimination[5+2] cycloaddition18.

-hydr ogenelimination-hydr ogenelimination
anti-Bredt olefin

The ruthecycle 81 cannot achieve the required
geometry.
-hydrogen elimination would generate anti-Bredt olefin.
Then, if even -hydroxy elimination is impssible,
what occurs ??

an inser tion
into the C-C bondof the cyclopr opane

methylenecyclopropane

18.

<How the reaction mechanism was confirmed ??>This Ru-catalyzed reaction proceeds without complications arising from self-condensation of either partner.
How does this practical reaction occurs ??
Path 1: allyl mechanism

Path 2: Ruthenacycle mechanism

Initially, path 1 seemed more possible than path 2 due to absence of homo-coupling product.
-If Path 2 operates, the formation of a ruthenacyclopentadiene should be preferred to that of a ruthenacyclopentene.
lead to homo-coupling products
lead to cross-coupling products
However, the validity of path 1 was questioned, because the regioselectivity about alkene was disrurbing.
-In light of other work, the formation of a -allylruthenium complex should undergo reductive elimination
with formation of the new C-C bond to the more substitued allyl terminus.
precedents of reductive elimination

Left: Tsuji, Y. et al. J. Organomet. Chem. 1989. 369, C51.
Reight: Trost, B. M. et al. J. Am. Chem. Soc. 1990. 112, 7809.
Path 1 was abondoned by the experimental support.
-To probe the involvment of a -allylruthenium chemistry, the reaction of (E)-2 butene was explored.
If path 1 operates, this reaction should result inthe same regioisomer as a 1-alkene: obtaining 15 as the product.
Spectral data clearly show the adduct is 14 and not 15.
This experiment suggests NOT involving -allylruthenium mechanismand supports path 2, which, furthermore, more consistently rationalizes the regioselectivity.

<Why self-coupling of alkyne does not dominate ??>If the ruthenacyclopentene and ruthenacyclopentadiene are in dynamic equilibrium,
the products then depend upon the rate of further reactions.
Fsst reversible formation
+

1

R

+

1

The unimolecular-hydrogen elimination

T he bimoledcular paths
f or the f urther reaction
NOT observed

the Alder ene type productnumerous side productsuch as arenes of cyclopentadienes(formed via the same mechanism as "scheme 10")
The unimolecula reaction rmay dominate overthe bimoledcular reaction.
So, although the rethenacyclopendadiene spiecies was formed,
only the cross-coupling product was obtained.

<the unique ability of a remote olefin>
The reaction of 1,7-octadiene proceeds with the enhanced selectivity for branched product.
If the reaction followed paths a and b exclusively...
The branched to linear ration should be the same as for 1-octene, which is not the case.
Other paths should be involved !

the symmetricbidentate coordination

If 22 was formed, steric factors arising from interaction of R and the olefin are eliminated from consideration.
The bias for branched vs linear product may simply reflect the intrinsic steric and electronic factors
associated with the tautomerization to the metallacycle (paths c and d)