Ru II H 2 (CO)(PPh 3 ) 3 CO 2 Me MeO 2 C Ru 0 (CO) n (PPh 3 ) 3-n MeO 2 C CO 2 Me 14e - (n = 0 or 1) 18e - CO 2 Me MeO 2 C L 3 Ru 0 CO 2 Me CO 2 Me 16e - 1-5 1-6 CO 2 Me MeO 2 C 1-7 1-8 1-9 1-10 1-11 1-12 Problem Session (2) -Answer- 2017. 6. 3. Tsukasa Shimakawa Topic: cyclobutane and cyclobutene derivatives in skeletal rearrangement 1. Cascade thermal isomerization of cyclobutane derivatives 1-1. Reaction mechanism -1- Margetic, D.; Warrener, R. N.; Butler, D. N.; Jin, C. M. Tetrahedron 2012, 68, 3306. OAc AcO 1-1 Ru 0 coordination OAc AcO Ru 0 migratory insertion OAc AcO reductive elimination OAc AcO OAc AcO H H Ru II CO 2 Me MeO 2 C H H Ru II CO 2 Me CO 2 Me H H CO 2 Me CO 2 Me Key Point: autoxidation, [1,5] hydrogen abstraction, [1,2] hydrogen shift 1,3-dipolar cycloaddition Ru 0 N N N Ph OAc AcO CO 2 Me CO 2 Me N N N Ph homolysis OAc AcO CO 2 Me CO 2 Me N N N Ph O O trapped by triplet oxygen OAc AcO O O CO 2 Me N N N CO 2 Me Ph OAc AcO CO 2 Me N N N CO 2 Me Ph - L, then 1-0 step 1 step 2 OAc AcO 1-1 1. RuH 2 CO(PPh 3 ) 3 (cat.) CO 2 Me MeO 2 C benzene, 80 °C, n/d 2. PhN 3 (5-10 eq. n/d), neat, rt, 10 days, 66% 3*. 140 °C, air, neat 20 min, 23% OAc AcO O CO 2 Me 1-2 (1.2 eq.) O O 1. release of repulsion with Ph group 2. formation of radical stablized by sp 3 N atom
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RuIIH2(CO)(PPh3)3
CO2MeMeO2C
Ru0(CO)n(PPh3)3-n
MeO2C CO2Me 14e- (n = 0 or 1)18e-
CO2MeMeO2C
L3Ru0
CO2Me
CO2Me
16e-
1-5 1-6
CO2Me
MeO2C
1-7 1-8
1-9 1-10
1-11 1-12
Problem Session (2) -Answer- 2017. 6. 3. Tsukasa Shimakawa
Topic: cyclobutane and cyclobutene derivatives in skeletal rearrangement1. Cascade thermal isomerization of cyclobutane derivatives1-1. Reaction mechanism
-1-
Margetic, D.; Warrener, R. N.; Butler, D. N.; Jin, C. M. Tetrahedron 2012, 68, 3306.
OAc
AcO
1-1
Ru0
coordinationOAc
AcO
Ru0
migratoryinsertion
OAc
AcO
reductiveelimination
OAc
AcO
OAc
AcO HH
RuII CO2Me
MeO2C
HH
RuII
CO2Me
CO2Me
HH CO2Me
CO2Me
Key Point: autoxidation, [1,5] hydrogen abstraction, [1,2] hydrogen shift
1,3-dipolarcycloaddition
Ru0 NNN
Ph
OAc
AcO
CO2MeCO2Me
NN
N
Ph
homolysisOAc
AcO
CO2MeCO2Me
NN
N
Ph
O O
trapped bytriplet oxygen
OAc
AcOO O
CO2Me
N
N N
CO2Me
Ph
OAc
AcO
CO2Me
N
N N
CO2Me
Ph
- L, then
1-0
step 1
step 2
OAc
AcO
1-1
1. RuH2CO(PPh3)3 (cat.)CO2MeMeO2C
benzene, 80 °C, n/d
2. PhN3 (5-10 eq. n/d), neat, rt,10 days, 66%
3*. 140 °C, air, neat20 min, 23%
OAc
AcOO
CO2Me
1-2
(1.2 eq.)
OO
1. release of repulsion
with Ph group
2. formation of radical
stablized by sp3 N atom
OAc
AcO
CO2Me
O
N N
H
O
HH
eliminationof N2
N2
orbital interaction(C-H HOMO and vacant 2p)
[1,2]-hydrogen shiftOAc
AcOO
CO2Me
1-2
1-2-2. Reaction mechanism for 1-3 and 1-41-2-2-1. tramsormation from 1-9 to 1-4
OAc
OAc
1-18
OAc
AcO
CO2MeCO2Me
NN
N
Ph
retroDiels-Alderreaction
[1,5] sigmatoropicrearrangement
OAc
OAc
1-4
1-13 1-14
1-15 1-16
1-17
1-16
N-1-17
1-9 -2-
bond rotation
OAc
AcO O
NN
1-16'
CO2MeOAc
AcO O
1-17
CO2Me
H
CO2Me
homolysis
OAc
AcO
OO
CO2Me
N
N N
CO2Me
PhH
[1,5] hydrogenabstraction
OAc
AcO
OHO
CO2Me
N
N N
CO2Me
Ph
OAc
AcO
CO2Me
O
OAc
AcOHO
CO2Me
N
N N
CO2Me
PhO
retro1,3-dipolar
cycloadditionN N
OAc
AcO
CO2Me
O
eliminationof N2
N2
H
[1,2]-hydrogen shiftOAc
AcOO
CO2Me
1-2
1-2. Discussion1-2-1. Explanation of geometric isomers
N
CO2Me
HO
Ph
aromatization isa driving force
step 3
OAc
AcO
1-3
NN
CO2Me
H
NMeO2C Ph
1-2-2-2. transformation from 1-9 to 1-3
OAc
AcO
CO2MeCO2Me
NN
N
Ph
retro1,3-dipolar
cycloaddition
OAc
AcO
CO2MeCO2Me
N
N
Ph
N
OAc
AcO
5-endo-dig
1-9 1-19
1-20
2-4
2-1 2-5 2-6
H
OAc
AcO
NN
1-19'
H
CO2Me
bond rotation
*
CO2Meintramolecularproton transfer
2. Asymmetric total synthesis of (+)-pleocarpenene by Snapper group2-1. Retrosynthesis
2-2. Reaction mechanism
Williams, M. J.; Deak, H. L.; Snapper, M. L. J. Am. Chem. Soc. 2007, 129. 486.
Key Point: Thermal rearrangement (fragmentation and Cope rearrangement)
H
Me
MeOH
MeHOH
2-3(+)-pleocarpenene
H
Me
MeOH
MeHO2-2
OTIPSH
AcO
thermalrearrangement Me Me
HO
cyclopropanationOTIPSH
AcO
[2+2]photocycloaddition
CO2MeO
O
MeO2C
4 photochemicalelectrocyclization
OTIPS
H
H
OTIPSH
AcO
1. EDA (5.0 eq.), Cu(acac)2 (5 mol%)CH2Cl2, reflux, 30 min;EtOH, rt, 15 min;NaOEt (5.0 eq.), 1.5 h (93%, 3 steps)
2. (COCl)2 (1.8 eq.), DMSO (2.0 eq.)THF, -62 °C, 30 min;Et3N (4.0 eq.), -62 °C to rt, 20 min;MeMgCl (10 eq.), -78 °C to rt, 12 h(79%, 3 steps)
3. DBU (15 mol%), benzene200 °C, 76%
H
Me
MeOH
MeHO
(-)-2-12-2
OTIPS
H
-3-
CuII(acac)2
* Salomon, R. G. and Kochi, K. J. Am. Chem.Soc. 1973, 95, 3300.Shirafuji, T.; Yamamoto, Y.; Nozaki, H. Tetrahedron. 1971, 27, 5353.
CuII
acac acac CuII
acac acac
EtO2C N2
- N2
CuII
acac
EtO2C O Me
O
Me
homolysisCuIacac
O Me
O
Me
+ CO2Et
MeO2C N Ph
NN
2-7 2-8
2-9active specie
Reduction from CuII to CuI*
H
CO2Me
Ph
H
H
HH H
H
H
H
H
2-10 2-11
2-13 2-14
2-15 2-16
2-17 2-4 2-18
2-18 2-19 2-20-1
EtO
O
NN
CuI
EtO
O
NN
CuI- N2
EtO
O
CuIII
OTIPSH
AcO
2-1
O
EtO
CuIII
OTIPSH
O
2-12
EtO2C
O Me OEt
OTIPSH
O
EtO2C
OTIPSH
HO
EtO2C
step 1
O
Cl
O
Cl
O
SMe Me
O
O
ClO
S
OTIPSH
O
EtO2C
SMe
H
- HNEt3
OTIPSH
O
EtO2C
HSMe
CH2
OTIPSH
EtO2C
O
- Me2S
OTIPSH
Me
HO
MeMe
HO
step 2
Cl
SCl
-CO2, -CO, -Cl
homolysis
H
H work-up
OTIPS
Me
HO
MeMe
HOHH
Discussion 1
3x MeMgCl
Discussion 2
Me
HO
OTIPSH
H
RH
OTIPS
HHH
conformationalchange
HH
H
HH
O
EtO2C
OTIPS
H
-4-
OTIPS
H
H H H
cyclopropanation(concerted)
H
H
2-17
scission
R R
OTIPS
H
large 1,3-diaxial interaction
Me
HO
2-20-2
2-3. Discussion2-3-1. Diastereoselectivity of cyclopropanation via metalcarbenoid
flip of radical
HHH
bond rotation
H
OTIPSCope rearrangement
H
H
H
H
Me
MeOH
MeHO
2-2
OTIPS
small 1,3-diaxial interaction
Me
HO
Me
HO
Davies, H. M. L.; Clark, T. J.; Church, L. A. Tetrahedron. Lett. 1989, 30, 5057.
+EtO2C CO2Et
N2 RhII2(OAc)4Ph Ph
CO2Et
Ph CO2Et
CO2Et
CO2Et96%
ratio: 8.3 : 1
Explanation of diastereoselectivity by Davies groupDavies, H. M. L. et al., J. Am. Chem. Soc. 1996, 118, 6897.Doyle, M. P. Chem. Rev. 1986, 86, 919.
RhIV
EWG
CO2Et
(Plane of ligand)
Ph
H
H
H
Ph group avoids bulky ligand plane and metal carbenoid(in case of trans olefin, dr ratio was increased)
RhIV
EWG
H
HPh
H
CO2Et
+
RhII
EWGHH
stablization of zwitterion like intermediate
PhH
CO2Et
CuIII
OAc
TIPSO
H
H
HEtO2C H
1. Path A (favored) 2. Path B (disfavored)
OAc
TIPSO
H
H
H
CuIII
H CO2Et
OTIPS
-5-
2-21-1
2-21-2 2-2
2-22 2-23 2-24
OTIPS
step 3
electrophilic carbene
2-22
TS-1
N-2-23
Ph
CO2Et
CO2Et
2-23
EWG: CO2Et
R R
H
H
R R
2-1
2-1
1
23
4
5
6776%
CuIII
H CO2Et
H H
TIPSO
OAc
large steric repulsion between ethyl esterand five membered ring
small steric repulsion between ethyl esterand five membered ring
CuIII
EtO2C HOAc
TIPSO
H
OTIPSH
2-9
EtO2C H
H
HAcO
OTIPSH
EtO2C H
H
HAcO
OTIPSH
Me
HO
MeMe
HOH
H
Me
MeOH
MeHO
OTIPSDBU (15 mol%)benzene, 200 °C1
234
6 75
-6-
2-9
2-4 2-2
H
disfavored path
path A path B
TS-2 TS-3
2-26
Cope rearrangement
H
H
H
2-3-2. Reaction mechanisam of thermal rearrangement
(1) Concerted path ([ 2s+ 2a] fragmentation)
Roth, W. R. et al., Chem. Ber. 1983, 116, 2717.
example of concerted [ 2s + 2a] fragmentation
HH
H
HH
H
4q+2 (s) = 14r (a) = 0
HH
HH
consistent with Woodward-Hoffmann rule(concerted pathway)
(1-1) [ 2s+ 2a] fragmentation (cleavage of C3-C7 and C4-C6)
Me
HO
OTIPSR H
Me
HO
OTIPS
R
Me
HO
OTIPSR
Cope rearrangement(chairTS)
trans olefin (disfavored intermediate)
OTIPS
HH
Me
HO
large 1,3-diaxial interaction
H
OTIPS Cope rearrangement
H
HH
small 1,3-diaxial interaction
Me
HOMeHO OTIPS
Reaction mechanism (from 2-27 to 2-30):
Other possibilities of [ 2s + 2a] fragmentation (3 types)* 5 membered ring cannot locate inside of newly formed 7 membered ring.
TS-4
OTIPS
Me
HO
Me
HO
OTIPS
R[ 2s + 2a]
OTIPS
Me
HO
H H
HOTIPS
Me
HO
HH
H
H
Me
HO
OTIPS Cope rearrangement
O
via
H
Me
MeOH
MeHO
OTIPS
chair TS
O O
boat TS
-7-
2-27 2-28 2-29 2-30
2-27 2-30
2-4 2-4-a 2-31
2-21-1 2-21-22-2
fast
2-4-b 2-32 2-32
2-33-1 2-33-2 2-34
[ 2s + 2a]H
R
R R
RR
R
R
H
H
4
63
7
H
H
R:Me
MeOH
(1-2) [ 2s+ 2a] fragmentation (cleavage of C1-C2 and C3-C7)
Me
HO
OTIPSR
Me
HO
OTIPS
R
Me
HO
OTIPS
H
OTIPSCope rearrangement
H
HH
small 1,3-diaxial interaction
Me
HO
MeHO OTIPS
Other possibilities of [ 2s+ 2a] fragmentation (3 types)
large 1,3-diaxial interaction
Me
HO
OTIPS
R
OTIPS
R
Me
HO
[ 2s + 2a]
impossible(trans olefin in 5 membered ring)
[ 2s + 2a]
impossible(trans double bond x 2 in 7 membered ring)
[ 2s + 2a]
HOTIPS
R
Me
HO
OTIPS
Me
HO H
OTIPS
MeHO
H
R
HH Cope rearrangement
boat TS
HH OTIPS
bond rotationHH
OTIPS
HH
OTIPS
H
Me
MeOH
MeHO
OTIPS
Cope rearrangement
-8-
2-4-c 2-35 2-35
2-36-1 2-36-2 2-36-2 2-34
2-4-d
2-4 2-4-e 2-21-1
2-21-2 2-2
2-4-f
H
[ 2s+ 2a] fragmentation (cleavage of C3-C7 and C4-C6) is NOT a reasonable path1. via trans olefin included in 7 membered ring intermediate2. Possibility of generating diastereomer 2-34
R
R
R R
R
Me MeMeHO HOHO
R R
3. Synthesis of bridged cyclopropane derivative3-1. Reaction mechanism
3-1
O
MeO2C CO2Me4. m-CPBA (1.0 eq.)CH2Cl2, rt, 1 h (89%)
5. Et2O, h , rt, 1 h (77%)6. NaOMe (3.0 eq.)MeOH, reflux, 1 h
O
O
MeO
MeO2CH
MeO2C+
OMeO
OMeMeO2C
O
O
H
3-2(35%)
3-3(31%)
1. cyclooctyne (1.8 eq.), , 2 h2. Et2O, h -20 °C , 20 h3. toluene or xylene,
H
Glaser, R.; Neumann, M.; Ott, F.; Peters, E. M.; Peters, K.;Schnering, H. G. V.; Tochtermann, W. Tetrahedron, 2001, 57, 3927.Tochtermann, W. and Rosner, P. Chem. Ber. 1981, 114, 3725.
Key Point: Pericyclic reaction ([4+2], [2+2], 4 electrocyclization), 3 -3 isomerization, [1,3]-hydride shift
O
MeO2CCO2Me
Diels-Alderreaction
O
MeO2C
MeO2C hO
MeO2C
MeO2C
OMeO2C
radical mechanismis also possibleO
MeO
OMeO2C
O
MeO
fragmentation[2+2]
cycloadditionformation of ylide(fragmentation)
1. via diradical (Homolysis of C3-C7 bond) or 2. [ 2s+ 2a] fragmentation of C1-C2,C3-C7 bond
Me
HO
OTIPS
R
Me
HO
OTIPS
R
impossible(trans olefin in 5 membered ring)
[ 2s + 2a]
[ 2s + 2a]
Me
HO
step 1 step 2
repulsion between "H" and"methylene-OTIPS" in TS
-9-
2-4-g
2-4-h
3-4 3-5
3-6 3-7
H
OTIPS
H
2-21-3
bond rotationMe
HO
OTIPS
large 1,3-diaxial interaction2-21-1
R
H
OTIPSCope rearrangement
H
HHsmall 1,3-diaxial interaction
Me
HO
MeHO OTIPS
2-21-2 2-2R R
O
MeO2C
MeO2CO
MeO2C
MeO2C O
MeO2C
MeO2C
ClO
O
H O
epoxidation(from convex)
O
MeO2C
MeO2C
O
O
MeO2C
MeO2H2C
O4 -electrocyclization(disrotatory)
H
MeO2C
O
CO2Me
H
O
fragmentation
OH
O
O OMe
OMe
-
OMeO
O O
MeO2C
O
MeO
OH
O
O OMeO
MeO
MeO OH
O
O OMeO
MeO
MeO
MeO
MeO H
1,4-addition
(release of strain
from sp2 to sp3)
OMeO
O
MeO2CMeO
O
Discussion 1
step 3
step 4 step 5
OMeO
O O
OMeMeO2C
MeOO
H H
OCO2Me
OMe
good: 1. stablized by anomeric effect2. No repulsion with tethered carbon chain
bad: 3. 1,3 like interaction
tethered carbon chain
OMeO
O
H
H
O
OMe
tethered carbon chain
O
lactone formation
methyl ester moiety:
OMe
OMe
O
OMe
-10-
3-8 3-9 3-9
Cl
O
HO 3-10 3-11 3-11
3-11 3-12 3-13
3-14 3-14'
3-15-
3-15- -A 3-16-
OMe
ring-opening
(formation ofoxonium cation) OMe
OMeO
O O
OMeMeO2C
MeO
3-15
from convex
MeO
O
H CO2Me
H
OCO2Me
OMe
formation ofoxonium cation
O
HCO2Me
H
CO2Me
O
O
MeO2C
H
MeO2C H
O
H H
CO2Me
tethered carbon chain
OMeO
O
MeO
H
good: 1. No 1,3-like interactionbad: 1. Not stablized by anomeric effect
2. repulsion between axial "H" and"tethered carbon chain"
H
CO2Me
tethered carbon chain
OMeOO
O
OMe
H
good: 1. No 1,3-like interactionbad: 2. Not stablized by anomeric effect
3. repulsion between axial "H" and"tethered carbon chain"
methyl ester moiety:
OMeO
O O
OMeMeO2C
OMeO
O O
MeO2CMeO
O
H
H
O
OMe
tethered carbon chain
O
OMe
OMe
O
OMe
O
H
H
O
OMe
tethered carbon chain
O
OMe
O
OMe1,4-addition OMeO
OMeMeO2C
O
O
Me
3-3
H
3-exo-tet
-11-
3-15- -B 3-15- -C
3-16- 3-17-
3-15- 3-15- -A 3-16-
3-16- ' 3-17-
OMeOMe
[1,3] hydrideshift
OMe OMe
MeO
H
H
O orbital overlapis insufficient
conformation is fixed due todouble bond (x2)
tethered carbon chaintethered carbon chain
MeO
3-2. Discussion3-2-1. Facial selectivity of protonation
OMeO
O OH
OMeMeO2C
MeO
OMe
OMeO
O OH
OMeMeO2C
MeO
3-exo-tetOMeO
O OH
OMeMeO2C
OMeO2C
MeO2C
HOMe
O
MeO2C
MeO2C
H
OOMe
O
H
H
OMe OMe
deprotonation
O
O
MeO
MeO2CH
MeO2C
3-2
OMeO
O O
OMeMeO2C
OMe
OMe
OMeO2C
MeO2C
HOMe
O
MeO2C
MeO2C
H
OOMeO
H
H
formation ofoxonium cation [1,3]-hydride shift
OMeO
O O
OMeMeO2C
OMe
O
H
O
OMeOMe
H
MeO2C
O
OMe
H
O
HMeO
CO2Me
CO2Me
OH
O
O OMeO
MeO
MeOO
H
O
O OMeO
MeO
MeO
MeO H
from convex
kinetically favored
OH
O
O OMeO
MeO
MeO
thermodynamically favored -12-
3-123-13- 3-13-
3-18 3-19 3-20
3-21
3-21 3-21-1
3-21-1
3-21-2
3-21-2
3-21-1 3-22
overlap of orbitalis sufficient
OMe
CO2Me
OMe
OMeO2C
H
CO2MeOMe
O
MeO2C
H
CO2Me
OOMe
O
H
H
deprotonationOMeO
O O
OMeMeO2C
OMe
OMe
OMeO
O OH
OMeMeO2C
OMe
OMeO
O O
OMeMeO2C
OMe
O
H
O
OMeOMe
H
MeO2C
O
OMe
H
O
HMeO
MeO2C
OMeO
3-2-2. Another mechanism of final step
-13-
3-3. Appendix (Proposed mechanism by author)
1. anti Baldwin's rule (3-endo-trig)
3-23 3-24
3-24 3-24-1 3-24-2
3-24-23-24-1
OMeO
OMeMeO2C
O
O
H
3-3
H
OMe
CO2Me
-14-
Appendix1. Problem 11-1. Another reaction mechanism to form 1-12 (Proposed by Prof. Inoue)
1-9
OAc
AcO
CO2MeCO2Me
NN
N
Ph
single electronoxidation
I-1
OAc
AcO
CO2MeCO2Me
NN
N
Ph
O O
OO
I-2
OAc
AcO
CO2MeCO2Me
NN
N
PhH
OO
I-3
OAc
AcO
CO2MeCO2Me
NN
N
H OPhO
1-12
OAc
AcOO O
CO2Me
N
N N
CO2Me
Ph
If single electron oxidation occurs, regioselectivity of this reaction is explained.
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