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Problem Session (5) 2017.10.28. Hiroaki Matoba
O
OBoc
OMe
1. BF3·OEt2, CH2Cl2, -78 °C;allylTMS, -78 to -20 °C
2. MsCl, Et3N, CH2Cl2, 0 °C to rt81% (2 steps)
3. BDSB, MeNO2, -25 °C to rt, 72%4. DIBAL, toluene, -78 °C to rt, 46%
OBr
O
H
Me
HO
OBn
O
O
1. NaN(TMS)2, THF, -80 °C;A, -80 to -15 °C;B, NaN(TMS)2, 18-crown-6
-80 to -70 °C, 64%
2. Pb(OAc)4, MeOH, benzene
0 °C, 95%
TBSO
PhMe2Si CHO
MeO2C
OBn
O
OH
O
SH
O
1. C, BF3·OEt2, CH2Cl2, -78 °C
quant., dr = 15:1
2. MeONHMe·HCl, i-PrMgCl, THF, -20 °C
3. Ac2O, DMAP, CH2Cl2, 67% (2 steps)
4. DIBAL, THF, -78 °C, 92%
5. D, DBU (cat.), IBX, DMSO, 73%
6. Cu(hfacac)2 (10 mol%), CH2Cl2reflux, 60%
O
Me
AcOOTBDPS
O
CO2Et
S
EtSEt
Br
SbBrCl5
BDSB
SiMe2t-Bu
O
PhMe2Si
A
O
NPh SO2Ph
B
MeO
OMe
OTBDPS
C
N2
OEt
O
D
O
O
F3C
F3C
CuIIO
O
CF3
CF3Cu(hfacac)2
Please provide each reaction mechanisms and explain the stereoselectivities.
1-1
2-1
3-1
1-2
2-2
3-2
Topics: Synthetic studies of Lauroxocanes
Introduction
Laurencia C15 acetogenins
Isolated from Laurencia sp. (red algae)
cyclic bromoether core (4-12 membered ring)
Laroxocanes
8-membered ring ether
the largest subset of the Laurencia C15 acetogenins family
Laurencin
Isolation
Laurencia glandulifera (Irie et al. TL, 1965, 16, 1091.) etc...
Total syntheses (method for constructionof oxecene core)
Masamune et al. TL, 1977, 18, 2507. (ring expansion: from bicyclo [3.3.1] nonane)
Murai and Tsushima TL, 1992, 33, 4345. (ring expansion: from bicyclo [4.2.0] octane)
Overman et al. JACS, 1995, 117, 5958. (acetal-vinylsulfide cyclizayion)
Holmes et al. JACS, 1997, 119, 7483. (Baeyer-Villiger oxidation: from cycloheptenone)
Crimmins and Emmitte OL, 1999, 1, 2029. (RCM)
Fujiwara et al. TL, 2005, 46, 6819. (RCM)
Kim et al. OL, 2005, 7, 75. (intramolecular amide enolate alkylation)
Formal syntheses
Palenzuela et al. Synlett, 1996, 983. (SN2 reaction of -sulfonyl anion to epoxide)
Hofmann and Krüger JACS, 1997, 119, 7499. (intramolecular allylboration)
Crimmins and Choy JACS, 1999, 121, 5653. (RCM)
Pansare and Adsool OBC, 2008, 6, 2011. (RCM)
Martin et al. JOC, 2010, 75, 6660. (RCM)
West et al. OL, 2017, 19, 552. (Stevens rearrangement: from bicyclo [4.3.0] nonane)
Laurefucin
Isolation
Laurencia subopposita (Wratten and Faulkner JOC, 1977, 42, 3343.) etc...
Total synthesis
Kim et al. JACS, 2008, 130, 16807. (intramolecular amide enolate alkylation)
Formal synthesis
Snyder et al. JACS, 2012, 134, 17714. (ring expansion: from bicyclo [3.3.0] octane)
Laurallene
Isolation
Laurencia nipponica (Fukuzawa and Kurosawa TL, 1979, 20, 2797.) etc...
Total syntheses
Crimmins and Tabet JACS, 2000, 122, 5473. (RCM)
Suzuki et al. TL, 2003, 44, 3175. (cyclization of hydroxy epoxide)
Kim et al. JACS, 2012, 134, 20178. (RCM)
Formal syntheses
Takeda et al. OL, 2008, 10, 1803. ([3+4] annulation)
Takeda et al. JOC, 2010, 75, 3941. ([3+4] annulation)
Problem Session (5) 2017.10.28. Hiroaki Matoba
O
Me
BrOAc
laurencin
OBr
O
H
Me
HO
laurefucin
Br
O
laurallene
O
•
Br
HH
HH 1
Answer
1. Formal synthesis of (±)-Laurefucin Snyder et al. JACS, 2012, 134, 17714key: Ring-expanding bromoetherification
H
O
O
OBoc
OMe
1. BF3·OEt2, CH2Cl2, -78 °C;allylTMS, -78 to -20 °C
2. MsCl, Et3N, CH2Cl2, 0 °C to rt81% (2 steps)
3. BDSB, MeNO2, -25 °C to rt, 72%4. DIBAL, toluene, -78 °C to rt, 46%
OBr
O
H
Me
HO
O
OBoc
MeO
BF3·OEt2
O
OBoc
MeOF3B
SiMe3
HOF3B
SiMe3
ClS
O O
H NEt3SO
O
EtS
Et
Br
SbBrCl5
BDSB
BDSB
O
OBoc
MeMsO
H
Br
discussion
O
O
HMsO
Br
Me
Ot-Bu
O
O HOMs
Me
Br
OO
Ot-Bu
H2O
O HOMs
Me
Br
OO
O
step 3
1-1 1-2
1-1 1-3
Felkin-Anh model
O
OBoc
MeOF3B
1-4
HH SiMe3
H2O
O
OBoc
MeHO
1-5
H
step 1
O
OBoc
MeMsO
H±H+
step 21-6
1-7 1-8
1-9 1-102
HOMs
Me
Br
OO
OAli-Bu2
DIBAL
1-11
1-12 1-13
O HOMs
Me
Br
Oi-Bu2AlO
Ali-Bu2
1-14
OBr
O
H
Me
i-Bu2AlO
1-15
H2O
OBr
O
H
Me
HO
1-2
OBr
O
H
Me
HO
laurefucin
2 steps
Kim et al
JACS, 2008, 130, 16807.
O HOMs
Me
Br
OO
OAl
i-Bu i-Bu
H
O HOMs
Me
Br
OO
OAl
i-Bu i-Bu
H
O HOMs
Me
Br
OO
OAl
H
1-10
O
3
Discussion: BDSB mediated cyclization
very effective reagent for cation- cyclization ineffective reagent for cation- cyclization
1. Properties and reactivity of BDSB (Snyder et al. ACIE, 2009, 48, 7899. JACS, 2010, 132, 14303.)
O
OBoc
MeMsO
H
O
OBoc
MeMsO
H
Br
O
OBoc
MeMsO
H
Br
O
O
HMsO
Br
Me
Ot-Bu
O
O
O
HMsO
Br
Me
Ot-Bu
O
O
HBr
OMs
H
O
H
Br
OMs
H H
2. Regio and stereoselectivity
1-6 1-7di-epi-1-7
1-8di-epi-1-8
disubstitutedmore electron rich olefin
di-epi-1-8 1-8
4
O HOMs
Me
Br
OO
O
di-epi-1-10
O
H
O
1-10
O
H
O
too far
OBr
Me
OO
HOMs
H
H
O
Br
R
BrO
Ot-Bu
R
5-exo 6-exo
1-16
O
Ot-Bu
discussion
t-BuMe2Si
PhMe2Si
O
O
OBnO
2-1 2-2
2-1
2. Formal synthesis of (+)-Laurallene Takeda et al. OL, 2008, 10, 1803.key: Brook rearrangement mediated [3+4] annulation
SiMe2t-Bu
O
PhMe2Si A
2-3
2-4 2-5
2-8step 1
Pb
OAc
OAc
OAcAcOIV
O
SiMe2Ph
O
TBSO
H H OBn
2-7
HOBn
OTBS
Si
O
O
H
Ph
O
N
Ph
SO2Ph
HOBn
OTBS
Si
O
O
H
Ph
OH
OBn
O
O
1. NaN(TMS)2, THF, -80 °C;A, -80 to -15 °C;B, NaN(TMS)2, 18-crown-6
-80 to -70 °C, 64%
2. Pb(OAc)4, MeOH, benzene
0 °C, 95%
TBSO
PhMe2Si CHO
MeO2C
OBn
O
HOBn
O
O
TMS TMSN
Na
OBn
O
O
SiMe2Ph
O
t-BuMe2Si OBn
O
O
O
O
TBSO
H H OBn
SiMe2Ph
too far
O
SiMe2Ph
O
TBSO
H H OBn
2-6
HOBn
OTBS
Si
O
O
H
Ph
ON
Ph
SO2Ph
2-5a 2-5b
2-6
HBrook rearr./
cyclopropanation
Cope rearr.
5
2-9 2-10
2-11
-Pb(OAc)2
2-2
TBSO
PhMe2Si CHO
MeO2C
OBn
O
2-2
Discussion: [3+4] annulation
1. 1,2-addition
Na
OBn
O
O
SiMe2t-Bu
O
PhMe2Si A
2-3
SiMe2Ph
O
t-BuMe2Si OBn
O
O
2-4 and 2-4a
O
H H
OBn
H
TBSO
O
SiMe2Ph
2-5-TS
SiMe2Ph
TBSO OBn
O
O
2-4a'
favoured 1,2-adduct
trans
‡
2-5a-TS
O
H H
TBSO
OH
H
OBn
SiMe2Ph
SiMe2Ph
TBSO OBn
O
O
2-4'
disfavoured 1,2-adduct
cis
OBn
O
2-12
TBSO
TBSO
10 steps 11 steps
Crimmins and Tabet
JACS, 2000, 122, 5473.
Br
O
laurallene
O
•
Br
HH
HH
HOBn
OTBS
Si
O
O
H
Ph
O Pb(OAc)2IV
OAc
OBn
OTBS
Si
O
O
H
Ph
O Pb(OAc)2IV
OBn
OTBS
PhMe2Si
OH
OBn
OTBS
PhMe2SiOHC
CO2Me
OH
‡
H
SiMe2Ph
TBSO OBn
O
O
2-4' and 2-4a'
MeOH
MeO
OO
PbIv(OAc)2
6
2. Brook rearrangement -> 1,2-addition
SiMe2Ph
O
t-BuMe2Si OBn
O
O
2-4
OBnO
2-5
H
O
O
t-BuMe2Si
PhMe2Si
Experiments to trap the intermediate (Takeda et al. JACS, 1995, 117, 6400. JACS, 1998, 120, 4947.)
O
SiMe2t-Bu
Me3Si
OLi
OH
Me3Si
t-BuMe2SiO O
TBSO
SiMe3
-80 °C, 30 min
2-13
2-14
2-15
47%
2-17
30%
2-16
0%
OH
SiMe3
TBSO
LDA, -80 °C, 5 min2-17: 25%2-16: 0%2-15: 67%
O
SiMe2t-Bu
Me3Si
OLi
-80 to -30°C40%
2-13
2-18
OH
SiMe3
TBSO
2-19
Attempt to isolate divinylcyclopropane for vinyl silane
Isolation of related cyclopropane intermediate
O
SiMe2t-Bu
Bu3Sn
OLi
-80 to -45°C
2-20
2-21
OH
SnBu3
TBSO
2-22
24%
Br
Br O
TBSO
2-23
5%
TBSO
2-24
16%
O Br
Bu3Sn
+ 2-20 (32%)
Isolation of divinylcyclopropane for vinyl stannane
Internal O-Si coordinated structure invokes the stereoselectivity.
7
OH
O
SH
O 1. C, BF3·OEt2, CH2Cl2, -78 °C, quant.
2. MeONHMe·HCl, i-PrMgCl, THF, -20 °C
3. Ac2O, DMAP, CH2Cl2, 67% (2 steps)
4. DIBAL, THF, -78 °C, 92%5. D, DBU (cat.), IBX, DMSO, 73%
6. Cu(hfacac)2 (10 mol%), CH2Cl2reflux, 60%
O
Me
AcOOTBDPS
O
CO2Et
S
MeO
OMe
OTBDPSMeO
OMe
OTBDPS
MeOOTBDPS
OH
O
SH
O
OH
O
S
O
TBDPSO
OMe
OH
O
S
O
TBDPSO
OMe
OH
O
S
O
TBDPSO
O
O
S
O
TBDPSO
O SO
O
TBDPSO
O
O
S
O
TBDPSO
O SO
O
TBDPSO
OH
O
S
O
TBDPSO
3. Formal synthesis of (+)-Laurencin West et al. OL, 2017, 19, 552.key: Stevenes rearrangement of sulfonium ylide
3-1 3-2
3-8
favoured
3-9
disfavoured
C
F3B
BF3
BF3·OEt2
3-3
3-4 3-5
3-1BF3·OEt2
3-73-6
3-7step 1
8
O
O
S
O
TBDPSO
O S
TBDPSO
OH
O
NOMe
O S
TBDPSO
OAc
O
NOMe
O S
TBDPSO
OAc
O
NOMe
AlH
i-Bu i-Bu
Al
i-Bu i-Bu
N2
OEt
O
O S
TBDPSO
OAc
O
CO2Et
N2
HN
N
O S
TBDPSO
OAc
O
CO2Et
N2
3-8
NOMeClMg
3-9
O S
TBDPSO
OAc
O
N2
OEt
O
H
D
DBU
O S
TBDPSO
OAc
OH
CO2Et
N2
3-11
3-12 3-13
3-14 3-15OI
O
OOH
step 2
O
O ON
N
O
O S
TBDPSO
OAc
O
NOMe
3-10 step 3
Al
H
step 4
I
OHOH
O
O
H
O S
TBDPSO
OAc
O
CO2Et
N2
3-173-16 step 5
DBU
9
O S
TBDPSO
OAc
O
CO2Et
N
N
O S
TBDPSO
OAc
O
CO2Et
N
N
CuI
O S
TBDPSO
OAc
O
CO2Et
CuI
O S
OAc
O
CuICO2Et
O S
OAc
O
CO2Et
TBDPSO
TBDPSO
O S
OAc
O
CO2Et
TBDPSO
O S
OAc
O
CO2Et
TBDPSO
O
Me
AcOOTBDPS
O
CO2Et
S
3-17 3-21
3-22 3-23
3-24 3-25
3-2 3-2
O
O
F3C
F3C
CuIIO
O
CF3
CF3
3-17
SET
O
O
F3C
F3C
CuIR
O
CO2Et
N
N
3-18
F3C
O O
CF3
Cu(hfacac)2 3-19 3-20
CuI
3-18
Stevens rearr.
solvent cage
O
Me
HOOTBDPS
3-26
8 steps
Holmes et al.
JACS, 1997, 119, 7483.O
Me
BrOAc
laurencin
6 steps
CuI
3-18
10
Discussion:
1. Cu(I) mediated decomposition of diazo compound
1-1. Cu(II) catalyzed cyclopropanation (Kochi et al. JACS, 1973, 95, 3300)
N2
O
OEt
5
CO2EtCu(OTf)2 (0.68 mmol)
1-octene/MeOAc (5/1)
D (mmol)
D 3-27
3-27
(mmol)
0.5
1.0Figure 4 indicated...
After addition of 1 eq. of D to Cu(II), the yield of 3-27 was
less than 20%. (1)
As the addition of D was continued, the yield of 3-27
eventually approached quantitative (based on the
incremental ammount of D added.) (2)
The addition of more Cu(II) caused a sharp drop in the
relative yield of 3-27 (3)
Cu(II) reacts with diazo compound firstly and generateCu(I), which is true active spiecies in this reaction.
1
2
Cu(OTf)2 was added
3
1-2. Reaction of Cu(II) salt and diazo compound (Nozaki et al. Tetrahedron, 1971, 27, 5353.)
PhPh
N2
Ph
OAc
OAc
Ph
Ph
PhCu(OAc)2
DMF/H2O, 25 °C70%
3-28 3-29
11
1-3. UV-VIS spectroscopy of Cu(acac)2 catalyzed cyclopropanation
(Safiullin et al. Kinetics and Ctalysis, 2008, 49, 43.)
MeO2C
N2
OMe
O
Cu(acac)2
CH2Cl2
3-30 3-31
As reaction proceeding, absorbance at 630 nm (derivedfrom Cu(II)) of the reaction mixtures were decreasing.
If, after the reaction, the reaction mixture is exposed toair, the absorbance of the solution will increase nearlyto its initial value.This is evidence that Cu(I) is oxidizedwith oxygen to Cu(II).
2. Solvent effect of Stevens rearrangement (Ollis et al. J. Chem. Soc., Perkin Trans 1, 1983, 1009.)
Ph
NMe2CH2COPh
HMe
Br
Ph*
NMe2CH2COPh*
HMe
Br
Ph HMe
COPhMe2N
Ph* = C6D5
Ph HMe
COPh*Me2N
Ph* HMe
COPhMe2N
3-32 3-32-d10
3-33 3-33-d5-1 3-33-d5-2
3-32:3-32-d10 = 1:1
base, solvent
In more viscous solvent, the reaction exhibits lower intermolecularity and higher stereoselectivity.
Ph* HMe
COPh*Me2N
3-33-d10
Ph HMe
COPhMe2N
Ph HMe
COPh*Me2N
Ph* HMe
COPhMe2N
epi-3-33 epi-3-33-d5-1 epi-3-33-d5-2
Ph* HMe
COPh*Me2N
epi-3-33-d10
crossover (intermolecular) productintra- or intermolecular product
12
