Lit. Seminar 061129

Kenzo YAMATSUGU (M2)CYCLOBUTADIENE IN ORGANIC SYNTHESISUsage of Unstable Intermediate: Cyclobutadiene as A Case

0. Introduction

OHH(CO)3Fe2 steps
HHOO

HHOH

H
O

(+)-Asteriscanolide
high reactivity

difficulty to use in synthesis
unstable species

unique reaction sequences

Contents
1. General feature of cyclobutadiene
2. Stabilization by iron tricarbonyl complex

3. Reaction sequences of cyclobutadiene
4. Total synthesis of (+)-Asteriscanolide

1. General feature of cyclobutadiene

Marc L. Snapper@Boston CollegeHuckel orbital energy+ antiaromataic+ unstability from ring strain+ rapid dimerization and oligomerization

α − 2βα − 2βα−βαcf. stable cyclobutadiene

αα+βα + 2βα + 2β

2. Stabilization by iron tricarbonyl complex+ in 1965, the first prepation of cyclobutadiene-iron tricarbonyl
Fe2(CO)9Cl
Cl

ref. JACS 1965, 87, 132.
(CO)3Festable pale yellow crystalline+ Molecular orbital of C4H4Fe(CO)3

ref. Inorg. Chem. 1979, 18, 1760.
Metalb1u

dxyδdzx, dyz

πdz2

σeg(2)eg(1)

a2u

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Molecular orbital diagram of C4H4Fe

Molecular orbital diagramof C4H4Fe and CO

Molecular orbital diagram of C4H4Fe(CO)3

1. near equality of the cyclobutadieneeg level and Fe 3d (dzx and dyz) level
2. Geometry of CO allows only b2, b1,and a1 (dz2, dxy, and dx2-y2) toparticipate in π back-donation.

FeCOCOCO

geometry of CO

3. d8 doesn't require metal-ring antibonding
orbitals to be occupied.

These three features make the complex stable.
+ compatible with many organic reactions*electrophilic reaction, Grignard reagent, reduction* cyclobutadiene-iron tricarbonyl complex is known
to decompose oxidatively.
(CO)3Fe+ Ce4+Fe2+ + CO ++ liberated cyclobutadiene can be trapped with several unsaturated compounds.
(CO)3Fe

COOMe

COOMeCANO(CO)3Fe

O

CAN

O

O

only activated dienophile can be used intermolecularly

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3. Reaction sequences of cyclobutadiene
3.1. Intramolecular cycloadditions between cyclobutadiene and alkenes

ref. JACS, 1996, 118, 9196.
JACS, 2002, 124, 14748.

H(CO)3Fe

HCAN
acetone, r.t., 15min

y. 85%OO# Precedents

pentaneO
sealed tubeo220 C, 90min(CO)3Fe

CANacetoneOOOOOH

y. 50%(CO)3Fe

1. hν
2. CANOy. 83% Tetrahedron Lett. 1974, 28, 2425.

# Scope and limitations
substrate preparation+ intramolecular = the key to success with unactivated olefin+ intermolecular cycloadditions ---------- oligomerization+ 11 & 14
transfer of stereochemical information ----concerted mechanism+ 20: sterically restricted tether ----------------oligomerization
higher temp. & short rxn. time ----------works well
+ 23: sterically encumbered alkene ----------two adjacentquaternarycarbon centers# Oxidative decomplexation of (CO)3Fe-cyclobutadiene complex
substrates prone to undergo intramolecular cycloaddition=
CAN (5eq.), acetone(1-2mM), r.t., 15minsubstrates less prone to undergo intramolecular cycloaddition=
trimethylamine-N-oxide(TMAO, 8-20eq.), acetone(2-20mM),
reflux, 6-24h

3/12No involvement of Fe in the cycloaddition# Tether effectpreliminary experiment

CAN* Three-atom heteroatom-containing tethers* Three-atom all-carbon tethers* Four-atom heteroatom-containing tethers* Four-atom all-carbon tethers+ Three-atom heteroatom-containing tethers

A: CAN, acetone, rt
B: CAN, DMF, 80oC
C: TMAO, acetone, reflux

A: CAN, acetone, rt
B: CAN, CH3CN, rt
C: CAN, DMSO-H2O, rt
D: TMAO, acetone, reflux*hydrolysis*cinnamyl alcohol wasrecoverd

allenesterically congestured

unactivated olefins: OKoxidant: CAN is OK

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+ Three-atom all-carbon tethers

A: CAN, r.t.
B: TMAO, reflux
C: CAN, reflux
unactivated alkene:CAN: X

transslightly activated alkene
CAN: OK
secondary orbital interaction ?

cistrans

activated alkene
good yieldsecondary orbital interaction ?

cis

restricted freedom of the tether

A: CAN, acetone
B: TMAO
C: CAN, MeOH

sp2+ reactivy
heteroatom-containg > all-carbon
shorter C-O lengths
compressed C-O-C bond angles

overall yield(ketalization)sp3

gem-disubstituted
cf. entry 1+ how to solve this low reactivity*electronic activation of dienophile*socondary orbital interaction*restriction in the freedom of tether*geminal substitution
*TMAO

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+ Four-atom heteroatom-containing or all-carbon tethers

A: CAN
B: TMAO
less reactive
transfreedomcisstrongly activated+ reactivity
three-atom > four-atom+ again, some activation (strongly in the case ofall-carbon case) is essential# Theoretical calculations

RB3LYP/6-31G(d) as implemented in Gaussian 98
These reactivity was supported by theoretical calculations.
H(A)

HH

Ovs(B)

HO

all-carbon

heteroatom-containing

short C-O bond=O[4+2], not [2+2]<All-carbon tether must be more compressed because of long C-C
bond at the expense of angle strain that destabilizes the B-TS.

6/12

HH(C)HO

Ovs(D)OOOHOOO

Unexpectedly, these activation energy
is higher than A-TS or B-TS. (cf. A: 9.1 kcal/mol)
Ester tether is too short to connect tworeacting groups without strain?
And because s-cis conformer is unfavorable?

>

Anyway, there is no inherent difference incyclization reactivity between C and D.
Low yield of D might be due to
1. less propensity to be oxidized
2. more electrophilicity of ester carbonyl(α-cation is stabilized by the complex)slightly<HH

(E)

HOH
OH

OH
OHvs(F)

H
O

sp3O

sp2E

Z

<<<EZ

11.2
13.6

<<clearly, sp2 carbon makes the compressed TS difficult

H

H

CO2MeH

MeO2C

Type I

CO2MeO(G)vsOType IIO(E)-alkene

H

Type I
Type IIO

H
H

CO2MeO(H)O

H

CO2Me(Z)-alkene

H

H
H

CO2Me

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The Type I transition structure is lower inenergy than the Type II transition.
(disagreement with experiment in H-TS)
Type I : Type II = 1.0 : 3.3(Table 6, entry 5)
E-alkene leads to lower energy transition
structure compared to Z-alkene.
A quantitative measurement of the factors(simplifed model)

Transition energy difference
I
Dienophile's energy differenceI
Endo/exo energy difference

2.8
I
1.6
I
0.6

=

=

Strain in the cis-transition structure

0.6(kcal/mol)

Conclusions
Oxidatively liberated cyclobutadiene could be trapped intramolecularly with olefins to afford
functionalized cyclobutene-containing cycloadducts.
This reaction was affected by several factors including1) oxidant (CAN vs TMAO)
2) electronical acitivation (conjugated olefin)3) tether length (heteroatom-containing vs all-carbon, 3 atoms vs 4 atoms)4) tether's freedom (sp2 vs sp3, restriction by phenyl group)5) alkene configuration (E vs Z)

3.2. Rapid entry into functionalized bicyclo[6,3,0] ring system
PrH

Pr

H
OTBS

OTBS

HClO

Cl

preliminary study using ethylene

PCy3RuPCy3 Phref. JACS 1997, 119, 1478.

H

200oC
sealed tube

OO

OTBS

PrH

85
bicyclo[6,3,0]

model study using substituted alkene(substituted alkene: regio- & stereo-chemical issue)
Z:E = 1:9
MeO

majorOMe

C6H13C6H13+

y. 66% (4:1)

C6H13MeO

minor

Z:E = 2:1

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substituted alkene (R = 4-penten-1-ol)
reconsideration of the steric factor

little regiocontrol(1.5:1 & 1.4:1)

OMe

conformation of the methoxy group may play a rolein dictating the reaction outcome ?

clear contrast between 17 and 21.
OMeH R

obstacle to Ru-center's access ?
Alkylidene complex was oserbed by 1H, 13C, 31P NMR, which does not undergo subsequent turnover.
PrH+HMeOPr

PCy3
ClRu
ClPCy3PhHHOPrRu
OTBS
Me ( )3H

HOOTBSMe ( )3+

PCy3Cl
RuCl
PCy3R

3.3. [2+2] photocycloaddition/thermal retrocycloaddition; a new entry to functionalized 5-8-5 ring system

PrHPrO

H+OMehνH H Me O
200-240oCHO

H H
Mesealed tube

ref. JACS 1999, 121, 4534.
OL 2001, 3, 2819.

Me O

PrHO

585H
Me5-8-5 ring system

JACS 2005, 127, 1201.

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Table 2. Thermal Fragmentation of Photoadducts

regioisomer

inversion

inversion

inversion

inversion

OPr

Meenchance the regioselectivity(steric repulsion?)++H H Me O

HH HMeOimprove yield(quaternary carbon prevents the carbonylgroup from participating unproductive reation??)+stereochemical inversion@C8 in entry 2 & 3@C14 in entry 4 & 5

Figure 2. Ortep plot of photocycloadduct 9.

Ocis,trans-1,5-cycloocatadiene

HMeRXYchairH?

OrelaxHMeRX

Y

cis,cis-1,5cycloocatadiene

Hboat+ Configuration of R determines which pathway (A orA') is prevailed. R favors exo face ?
+ cis,trans-1,5-cyclooctadiene relaxes leading tocis,cis-1,5-cycloocatadiene through rearrangement.
3.4. Approach to bicyclo [5,3,0] ring system through cyclopropane opening
HHOH HPrCH2I2, Et2Znr.t., 12hH
HOPr

Pr
130-250oC

ref. JACS 2001, 123, 5152.
OL 2005, 7, 5785.
OL 2006, 8, 5183.

H

75

bicyclo [5,3,0]
O

10/12

+ C1 substituent influence the facility of the rearrangement.

inversion

involvement of the bonds neghboring the C1 substituent+ inversion @ C10

boatchair+ C1 substituent:influence the formation and reactivity of diradical
A' and A"?
+ inversion: B to C
(preference for cis,cis-cycloheptadiene ?)+ entry 6: unfavorable 1,3-interactions @ A" or B ?
+ Lewis acid-mediated fragmentations are also possible.
Table 1. Lewis Acid-Mediated Isomerizations of Cyclopropyl Systems

H H

H
H
HOH H

R

PCC
r.t.

H
H
ORR

H

BF3.Et2O
0 oC
10-20 minretentionO* low temp. & short time
* retention of configuration* β-substituent is OK.

β-substituted* approapriately positioned carbonyl is necessary* entry 7: acid sensitivity (epimerization & conjugation)* C3-C7 bond is weakened by Lewis acid-carbonyl interaction.
* relaxation from boat 30 to chair 31* strain releasing opening from 31 to 32

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+ Oxepines are also available.
HH H

Rm-CPBA

RO

H

H
H

O

R

R200oCH

O+OO

O

4. Total synthesis of (+)-Asteriscanolide
OH

MeH

O

ref. JACS 2000, 122, 8071.

MeH

Me(CO)3Fe(CO)3Fe
H

O

H

H

H
OO

H

H

O

COOMe[O]O(+)-Asteriscanolide
CBS red.
exoHH

cyclobutadiene Diels-Alderring-opening metathesis
sequenceHOstability of cyclobutadiene-irontricarbonyl complex

XO exoTotal Syntheis of (+)-Asteriscanolide
OMeMeOH2) BH3.OEt2, THF,(S)-B-Me-CBS (10 mol%)

1) LDA, TMSCl, Et3N;
Pd(OAc)2 (10 mol%)benzoquinone
60%

MeMe56%, 94% ee

1O2hν, PhH;
Fe2(CO)9, 50oC
64%

COOMeO1) LAH, BF3.OEt2
93%2) Me2NCH2NMe2,
H3PO4, AcOH
100oC, 67%

COOMe

43(CO)3Fe

H H

MeMe3NO, acetone
56oC, 63%

H(CO)3FeOHHOOHMeHO91) Red-Al, CuBr;
AcOH, THF, 89%
2) BH3.THF, THF;
PCC, MS 4A, CH2Cl260%

5MeH

7H

PCC, Py.
MS 4A
CH2Cl279%NMe2ethylene, 8,PhH, 50-80oC
74%

H

MeMeI, THF;
NaH, 2, THF/DMF
50%

MeO

6(CO)3Fe

H

O

O

N Mes
Mes N
Cl RuClPh
PCy3H

88

Mey. 3.9% for 9 steps

HHO

10(+)-Asteriscanolide

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