recent progress in the total synthesis of typical lignans
DESCRIPTION
Recent progress in the Total Synthesis of typical lignans. Pusheng Wang 2012-11-10. Ligin ( 木质素 ) and Lignan ( 木 酯 素 ) . 木质素（ Ligin ）是 由四种醇单体（对香豆醇、松柏醇、 5- 羟基松柏醇、芥子醇）形成的一种复杂酚类 聚合物。. 木脂素（ Lignan ）是一类由两分子苯丙素衍生物（即 C6-C3 单体）聚合而成的天然化合物，多数呈游离状态，少数与糖结合成苷而存在于植物的木部和树脂中，故而得名。通常所指其二聚体，少数可见三聚体、四聚体。. - PowerPoint PPT PresentationTRANSCRIPT
Recent progress in the Total Synthesis of typical lignans
Pusheng Wang2012-11-10
2
Ligin (木质素 ) and Lignan (木酯素 )
木质素（ Ligin）是由四种醇单体（对香豆醇、松柏醇、 5-羟基松柏醇、芥子醇）形成的一种复杂酚类聚合物。
木脂素（ Lignan）是一类由两分子苯丙素衍生物（即 C6-C3单体）聚合而成的天然化合物，多数呈游离状态，少数与糖结合成苷而存在于植物的木部和树脂中，故而得名。通常所指其二聚体，少数可见三聚体、四聚体。
3
(-)-Steganone
O
O
OO
MeO
MeO
MeO
O
J. Am. Chem. Soc. 2000, 122, 52-57
(+)-Chicanine
OHO
MeO OO
Tetrahedron Lett. 2011, 52, 3005-3008
(-)-Podophyllotoxin
O
OO
OH
O
OMeOMeMeO
J. Org. Chem. 2000, 65, 847-860
(-)-Sacidumlignans B
HO
MeO
OHOMeMeO
OMe
O
OMeHO
MeO
MeO
HOOMe
(-)-Sacidumlignans D
(-)-Picropodophyllin
O
OO
OH
O
OMeOMeMeO
J. Org. Chem. 2012, 77, 1566.1571
(-)-talaumidin
OHO
MeO OO
Tetrahedron Lett. 2006, 47, 3979-3983
(+)-Magnolone
O
HOO
OO
OMe
OMe
Tetrahedron Lett. 2010, 51, 2975-2978
(+)-veraguensin
OMeO
MeO OMeOMe
Tetrahedron Lett. 2010, 51, 6924-6927
(+)-virgatusin
OMeO
MeO OO
MeO OMe
Chem. Commun. 2009, 5135-5137
(+)-wikstromol
O
OH
OMeOOH
HO
MeO
Tetrahedron: Asymmetry 2001, 12, 987-989
(+/-)-Paulownin
O
O
H
HO
O
O O
O
J. Org. Chem. 2008, 73, 6268-6278
Carpanone
O
O
O
O
OO
H
H
Org. Lett. 2008, 10, 4097-4100
Dibenzocyclooctadiene
OO
O
MeOMeO
OO
O
R
J. Org. Chem. 2005, 70, 8932-8941
Eupomatilones
OO
R2R1
MeO
R3R4
R5
Org. Lett. 2002, 6, 4025-4028J. Org. Chem. 2007, 72, 8724-8736
(-)-Wodeshiol
O
O
HO
OH
O
OO
O
J. Chem. Sci. 2011, 123, 327-330
A B
C DE
Total synthesis of typical ligans in recent years
4
Part A | (-)-Podophyllotoxin and (-)-Picropodophyllin
David B. Berkowitz, J. Org. Chem. 2000, 65, 847-860
O
OO
OH
O
OMeOMeMeO
O
OO
OH
O
OMeOMeMeO
O
O
OMe
OMe
OH +
CO2Me
CO2Me
O
O CO2Me
CO2MeO
Pd/C
H2
HOAc O
O CO2Me
CO2MeO
endo only92% 99%a. LAHb. Ac2O,pyr.
O
O CH2OAc
CH2OAcO
PPL(enzyme)O
O CH2OAc
CH2OHO
95%ee
[4+2]
a. TIPSCl, imid.b. K2CO3,MeOHc. Swern OxidationO
O CHOO
OTIPS
Retro-MichaelMeONaMeOH
O
O CHO
OTIPSOH a. SEMCl, DIPEAb. NaClO2c. CDI, 2-oxazolidinone O
O
OSEM OTIPS
N
O O
O
a. ArMgBr, CuCNb. TBAF
O
OO
OSEM
O
OMeOMeMeO
LDA
O
OO
OSEM
O
OMeOMeMeO
EtSHMgBr2
EtSHMgBr2
(-)-Podophyllotoxin
(-)-Picropodophyllin
SEM = OTMS
5
Part A | (−)-Sacidumlignans B and D
C. V. Ramana, J. Org. Chem. 2012, 77, 1566-1571
O
OBnBr
MeOOAllyl
OMe+
n-BuLiOH
OAllylMeO OMe
MeO
AllylOOMe
a. Pd(OAc)2,PPh3 N,N-DMDAb. TBSCl, imid.
OH
OTBSMeO OMe
MeO
TBSOOMe
a. OsO4, NaIO4b. Ag2CO3-Celitec. LiHMDS, MeOTf
TBSO
MeO
OMe
MeO
TBSOOMe
O O LAH
TBSO
MeO
OMe
MeO
TBSOOMe
OH OH
HO
MeO
OMe
MeO
HOOMe
O
a. TFA, DCMb. TBAF
(.)-Sacidumlignan Da. LAHb. Et3SiHc. IBX
a. p-TSAb. TBAF
HO
MeO
OMe
MeOOH
OMe
TBSO
MeO
OMe
MeOOTBS
OMe
O
(.)-Sacidumlignan B
N
O O
O
R
+
Br
N,N-DMDA
N OH
OH
6
Part B | (-)-talaumidin
Yoshiyasu Fukuyama, Tetrahedron Lett. 2006, 47, 3979-3983
MeO
BnO
CHO
+
O
N O
O
Bn
MeO
BnO
OH O
N O
O
Bn
a. TBSOTfb. LiBH4c. DMSO, (COCl)2
MeO
BnO
OTBS
O
a. MeMgBrb. DMSO, (COCl)2c. Tebbbe reagent
MeO
BnO
OTBS 9-BBNthen H2O2
MeO
BnO
OTBS
a. MgCl2, TMSCl, Et3N
OH
b. Py/HF
a. PDCb. NaClO2c. Py/HF
O OBnO
MeOMeONaMeOH
O OBnO
MeO
a. DIBAL-Hb. CH(OMe)3, p-TSA
O OMeBnO
MeO O
O
SnCl4
Pd(OH)2H2EtOH
OBnO
MeO
OO
(-)-talaumidin
anti-Aldol
7
Part B | (+)-Chicanine
Yoshiyasu Fukuyama, Tetrahedron Lett. 2011, 52, 3005-3008
OHO
MeO OO
MeO
BnO
CHO
+
O
N O
O
Bn
Bu2BOTfDIPEA MeO
BnO
OH O
N O
O
Bn
a. TBSCl, DMFb. NaBH4c. DMP
MeO
BnO
OTBS
O
a. MeMgBrb. DMPc. Tebbbe reagent
MeO
BnO
OTBSa. 9-BBN then H2O2b. DMPMeO
BnO
OTBS
CHO
O
O
MgBr
MeO
BnO
OTBS
OHO
O
a. Pd/C, H2b. TsClc. TBAF
MeO
TsO
OH
OHO
Oa. Tsunoda reagent Me3P=CHCNb.MeONa
(+)-chicanine
8
Examination of the Mitsunobu etherification
9
Part B | (+)-veraguensin
Subrata Ghosh, Tetrahedron Lett. 2010, 51, 6924-6927
(+)-veraguensin
OMeO
MeO OMeOMe
OHOO
OO
OH
a. NaIO4b. Ph3P=CHCO2Etc. LAH O
O OH
MeCH(OEt)3EtCO2H
140 oCJohnson-Claisen rearrangement
OO
CO2Et
O
OEt
R
H
CHO
OBnOMe
LDA
OO
CO2EtOH
Ar
a. HOAc, NaIO4b. MeOH-HCl
O
CO2Et
MeO
OMeOBn
a. OsO4, NaIO4b. NaBH4, then silica gel
OMeO
OMeOBn
O Oa. LAHb. MsClc. LAH
OMeO
OMeOBn
a. HOACb. Jones Oxidation
O
OMeOBn
O
MeO
MeO
Li
OMeO
MeO OMeOMeOH
a. Pd(OH)2, H2b. MeI, NaH
CO2Et
MeOArHO
10
Part B | (+)-virgatusin
Jeffrey S. Johnson, Chem. Commun. 2009, 5135-5137
(+)-virgatusin
OMeO
MeO OO
MeO OMe
CHO
OMeOMe
MeO2C CO2Me
Br+
NH
Ph
OTMSPh (30%)
CHO
CO2MeCO2Me
MeOOMe
a. NaClO2, H2O2b. BnBr, Et3N
CO2Bn
CO2MeCO2Me
MeOOMe
OO
CHO
AlCl3(10%)DCM
O
BnO2C
MeO
MeO OO
CO2MeCO2Mea. Pd/C, H2
b. KOAc, DMSO/H2O 100 oC
O
HO2C
MeO
MeO OO
CO2Mea. LAHb. NaH, MeI
11
Part B | (+)-Magnolone
Ganesh Pandey, Tetrahedron Lett. 2010, 51, 2975-2978
(+)-Magnolone
O
HOO
OO
OMe
OMe
NO
O OPO
OMeOMe
Bn
OOTBS+
K2CO3NO
O O
Bn
OTBS
a. CH2=CHMgBr, CuIb. ArCHOc. TiCl4
Ar =O
O
O
O
OO
NO
OO
Bn
OTBS
Ar OTi
NO
OO
Bn
OTBS
Ar
N
OO
Bn
a. LiBH4b. TBSCl, imid.c. OsO4, NMOd. NaIO4
O
TBSOO
OO
MeO
MeO
Li
b. IBXc. TBAF
a.
Sequential Michael-Evansaldol cyclization
12
Part B | (+)-wikstromol
Michael Sefkow, Tetrahedron: Asymmetry 2001, 12, 987-989
(+)-wikstromol
O
OH
OMeOOH
HO
MeO
iPrO2C
OHCO2
iPr +MeO
BnO
Br LHMDS
THF
iPrO2C
OHCO2
iPr
OMeOBn
a. KOH, EtOHb. tBuCHO, p-TSA CO2H
OMeOBn
OO
tBu
O
LHMDSMeO
BnO
Br
CO2H
OMeOBn
OO
tBu
O
OBn
OMe
a. BH3.SMe2
b. 4M HCl
O
OBn
OMeOOH
BnO
MeO
Pd/C, H2
HO2C
OHCO2H
malic acid,苹果酸
13
Part C | (+/-)-Paulownin
Steven R. Angle, J. Org. Chem. 2008, 73, 6268-6278
(+/-)-Paulownin
O
O
H
HO
O
O O
O
OO
OH TIPSClDMAP
OO
OTIPS+
OTESO
BF3.OEt2,
DBMP,
N
DBMP
O
TIPSOO
TESO
O
LA
O
TIPSOHO
OO
a. DMPb. HF-Py
O
HOO
OO
OO
O CCl3
NH
TMSOTf
O
OO
OO
O
O
hv, PhH More details about Type II Photocyclization Reactioncan see: J. A m. Chem. Soc. 1990, 112 , 3464-3466
14
Part C | (-)-Wodeshiol
Oee Sook Park, J. Chem. Sci. 2011, 123, 327-330
NHO
O
Bn
a. n-BuLi
b.COCl
COCl
O
NO
NO
OO
OBn
Bn a. Bu2BOTf, DIPEA piperonal
b. KH2PO4(aq), H2O2
(-)-Wodeshiol
O
O
HO
OH
O
OO
O
O
O
O
OO
O
O
OH
H
LDA, MoOPH/THF
O
O
O
OO
O
O
OHO
OH
a. DIBAL-Hb. Et3SiH, BF3
.OEt2
15
Part D | Carpanone
Craig W. Lindsley, Org. Lett. 2008, 10, 4097-4100
Carpanone
O
O
O
O
OO
H
H
OH
O
OOH
OO
+
CuCl2 (4eq.)tert-butyl amine (16eq.)
air, MeOH, rtO
O
O
OO O
OH
O
O
K2CO3allyl bromide
O
O
O
DMF, 190 oC
OH
O
O
tBuOKDMSO
OH
O
O
Chapman, J. Am. Chem. Soc. 1971, 93, 6697-6698
OH
O
O
tBuOK
OK
O
O OH
O
O
?
16
Part E | Dibenzocyclooctadiene
Robert S. Coleman, J. Org. Chem. 2005, 70, 8932-8941
O
OOMe
Br
CHO+ Si
Cl
Br
Br
a. DCM, -78 oCb. TBSCl 2,6-lutidine O
OOMe
Br
OTBS
a. 9-BBN, THF O
OOMe
Br
OTBS
b. Pd(PPh3)4, NaOHO
OOMe
Br OO
OMe
NBSCHCl3
O
OOMe
Br
OTBS
OO
OMe
Br
Dibenzocyclooctadiene
OO
O
MeOMeO
OO
O
R
OTBS
OO
MeO
MeO
OO
LiLiCuCN
OTBS
OO
MeO
MeO
OO
Cu1,3-dinitrobenzene
OTBSO
O
MeOMeO
OO
a. TBAFb. PPh3, DIAD, RCO2H
Oxidative Cuprate Biaryl Coupling
96% ee
tBuLi
17
Part E | Eupomatilones
Robert S. Coleman, Org. Lett. 2002, 6, 4025-4028 J. Org. Chem. 2007, 72, 8724-8736
OO
R2R1
MeO
R3R4
R5
O
Ar
OHO
Ar
O
HAr
In
O
Ar
O O
HAr O
OMe
B(OR*)2
eupomatilones 4, 6
eupomatilones 1, 2, and 5
eupomatilones
18
Part E | Eupomatilones
Robert S. Coleman, Org. Lett. 2002, 6, 4025-4028
OO
HO CHO
a. NBSb. Me2SO4, K2CO3
OO
MeO CHOBr
In2Br33
a.
b. TBSOTf
OO
MeOBr OTBS
Br
MeOOMe
OMe
a. tBuLib. CuCNc. O2
OO
MeOOTBS
OMeMeO OMe
a. 9-BBNb. H2O2, NaOHc. TBAFd. TEMPO, NCS
Eupomatilone 4
OO
MeO
MeOOMe
OMe
OO
19
Part E | Eupomatilones
Robert S. Coleman, J. Org. Chem. 2007, 72, 8724-8736
MeO CHOBr
Eupomatilone 5
O
O
a. L-selectrideb. PhMgBrc. NaOH, H2O2
OHOH
B BN
N N
NO
OO
OB B CuCl, LiCl, KOAc
CO2MeOAc
OO B
MeO2C
Br OO
MeO
OMeMeO
OMeMeO
100% ciser = 77:23
Pd2(dba)3S-PhosK3PO4
O
O
B(OH)2O
O
MeO
OMeMeO
OO
O
O B
OH
CO2Me
OMeOMe
OMe
Br
Transition State
20
Part E | (-)-Steganone
Gary A. Molander, J. Am. Chem. Soc. 2000, 122, 52-57
(-)-Steganone
O
O
OO
MeO
MeO
MeO
O
Br
MeO
MeO
OMe
CHO
(OC)3Cr
NaBH4
Br
MeO
MeO
OMe(OC)3Cr
OH
OO
B(OH)2
CHO
Pd(PPh3)4, Na2CO3
MeO
MeO
OMe(OC)3Cr
OH
OO
CHO
MeO
MeO
OMe(OC)3Cr
OH
OO
CHO
MsClNEt3HBr
MeO
MeO
OMe(OC)3Cr
Br
OO
CHOO
O
Bu3Sn
Pd2(dba)3, AsPPh3MeO
MeO
OMe(OC)3Cr
OO
CHO
O
OSmI2
OH
O
OO
MeO
MeO
MeO
O
(OC)3Cr
PCCNaOAc
O
O
OO
MeO
MeO
MeO
O
O
O
OO
MeO
MeO
MeO
O
DBU+
21
Summary
Main source of chirality:
NO
O
R
From natural products:
Substrate induced:
HO2CCO2H
OH
Asymmetric Organoatalysis:NH
PhPh
OTMS
EnzymeBiocatalysis
SiR1
R2 Cl*
sugar
Main Tools
Need to developed