recent progress in the total synthesis of typical lignans pusheng wang 2012-11-10
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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
O
O
MeO
MeO
MeO
O
J. Am. Chem. Soc. 2000, 122, 52-57
(+)-Chicanine
OHO
MeO O
O
Tetrahedron Lett. 2011, 52, 3005-3008
(-)-Podophyllotoxin
O
OO
OH
O
OMe
OMeMeO
J. Org. Chem. 2000, 65, 847-860
(-)-Sacidumlignans B
HO
MeO
OH
OMeMeO
OMe
O
OMeHO
MeO
MeO
HO
OMe
(-)-Sacidumlignans D
(-)-Picropodophyllin
O
OO
OH
O
OMe
OMeMeO
J. Org. Chem. 2012, 77, 1566.1571
(-)-talaumidin
OHO
MeO O
O
Tetrahedron Lett. 2006, 47, 3979-3983
(+)-Magnolone
O
HO
O
O
O
OMe
OMe
Tetrahedron Lett. 2010, 51, 2975-2978
(+)-veraguensin
OMeO
MeO OMe
OMe
Tetrahedron Lett. 2010, 51, 6924-6927
(+)-virgatusin
OMeO
MeO O
O
MeO OMe
Chem. Commun. 2009, 5135-5137
(+)-wikstromol
O
OH
OMeO
OHHO
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
O
O
O
MeO
MeO
O
O
O
R
J. Org. Chem. 2005, 70, 8932-8941
Eupomatilones
O
O
R2
R1
MeO
R3
R4
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
OMe
OMeMeO
O
OO
OH
O
OMe
OMeMeO
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
OSEMOTIPS
N
O O
O
a. ArMgBr, CuCNb. TBAF
O
OO
OSEM
O
OMe
OMeMeO
LDA
O
OO
OSEM
O
OMe
OMeMeO
EtSHMgBr2
EtSH
MgBr2
(-)-Podophyllotoxin
(-)-Picropodophyllin
SEM = OTMS
5
Part A | (−)-Sacidumlignans B and D
C. V. Ramana, J. Org. Chem. 2012, 77, 1566-1571
O
OBnBr
MeO
OAllyl
OMe+
n-BuLi
OH
OAllyl
MeO OMe
MeO
AllylO
OMe
a. Pd(OAc)2,PPh3 N,N-DMDAb. TBSCl, imid.
OH
OTBS
MeO OMe
MeO
TBSO
OMe
a. OsO4, NaIO4b. Ag2CO3-Celitec. LiHMDS, MeOTf
TBSO
MeO
OMe
MeO
TBSO
OMe
O O LAH
TBSO
MeO
OMe
MeO
TBSO
OMe
OH OH
HO
MeO
OMe
MeO
HO
OMe
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
O
O
(-)-talaumidin
anti-Aldol
7
Part B | (+)-Chicanine
Yoshiyasu Fukuyama, Tetrahedron Lett. 2011, 52, 3005-3008
OHO
MeO O
O
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. DMP
MeO
BnO
OTBS
CHO
O
O
MgBr
MeO
BnO
OTBS
OH
O
O
a. Pd/C, H2b. TsClc. TBAF
MeO
TsO
OH
OH
O
O
a. 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 OMe
OMe
OHOO
OO
OH
a. NaIO4b. Ph3P=CHCO2Etc. LAH
OO OH
MeCH(OEt)3EtCO2H
140 oC
Johnson-Claisen rearrangement
OO
CO2Et
O
OEt
R
H
CHO
OBn
OMeLDA
OO
CO2Et
OH
Ar
a. HOAc, NaIO4b. MeOH-HCl
O
CO2Et
MeO
OMe
OBn
a. OsO4, NaIO4b. NaBH4, then silica gel
OMeO
OMe
OBn
O Oa. LAHb. MsClc. LAH
OMeO
OMe
OBn
a. HOACb. Jones Oxidation
O
OMe
OBn
O
MeO
MeO
Li
OMeO
MeO OMe
OMeOH
a. Pd(OH)2, H2b. MeI, NaH
CO2Et
MeOArHO
10
Part B | (+)-virgatusin
Jeffrey S. Johnson, Chem. Commun. 2009, 5135-5137
(+)-virgatusin
OMeO
MeO O
O
MeO OMe
CHO
OMe
OMe
MeO2C CO2Me
Br+
NH
Ph
OTMSPh (30%)
CHO
CO2Me
CO2Me
MeO
OMe
a. NaClO2, H2O2b. BnBr, Et3N
CO2Bn
CO2Me
CO2Me
MeO
OMe
OO
CHO
AlCl3(10%)DCM
O
BnO2C
MeO
MeO O
O
CO2MeCO2Mea. Pd/C, H2
b. KOAc, DMSO/H2O
100 oC
O
HO2C
MeO
MeO O
O
CO2Mea. LAHb. NaH, MeI
11
Part B | (+)-Magnolone
Ganesh Pandey, Tetrahedron Lett. 2010, 51, 2975-2978
(+)-Magnolone
O
HO
O
O
O
OMe
OMe
NO
O O
P
O
OMeOMe
Bn
O
OTBS+K2CO3
NO
O O
Bn
OTBS
a. CH2=CHMgBr, CuIb. ArCHOc. TiCl4
Ar =O
O
O
O
O
O
NO
OO
Bn
OTBS
Ar OTi
NO
OO
Bn
OTBS
Ar
N
OO
Bn
a. LiBH4b. TBSCl, imid.c. OsO4, NMOd. NaIO4
O
TBSO
O
O
O
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
OMeO
OHHO
MeO
iPrO2C
OH
CO2iPr +
MeO
BnO
Br LHMDS
THF
iPrO2C
OH
CO2iPr
OMe
OBn
a. KOH, EtOH
b. tBuCHO, p-TSA CO2H
OMe
OBn
OO
tBu
O
LHMDSMeO
BnO
Br
CO2H
OMe
OBn
OO
tBu
O
OBn
OMe
a. BH3.SMe2
b. 4M HCl
O
OBn
OMeO
OHBnO
MeO
Pd/C, H2
HO2C
OH
CO2H
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+
O
TESO
BF3.OEt2,
DBMP,
N
DBMP
O
TIPSOO
TESO
O
LA
O
TIPSOHO
O
O
a. DMPb. HF-Py
O
HOO
O
O
OO
O CCl3
NH
TMSOTf
O
OO
O
O
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
N
O
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
O
H
H
LDA, MoOPH/THF
O
O
O
OO
O
O
O
HO
OH
a. DIBAL-H
b. 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
O
OH
OO
+
CuCl2 (4eq.)tert-butyl amine (16eq.)
air, MeOH, rt
O
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
O
OMe
Br
CHO
+ SiCl
Br
Br
a. DCM, -78 oC
b. TBSCl
2,6-lutidineO
O
OMe
Br
OTBS
a. 9-BBN, THF O
O
OMe
Br
OTBS
b. Pd(PPh3)4, NaOH
O
O
OMe
Br OO
OMe
NBSCHCl3
O
O
OMe
Br
OTBS
OO
OMe
Br
Dibenzocyclooctadiene
O
O
O
MeO
MeO
O
O
O
R
OTBS
OO
MeO
MeO
OO
LiLiCuCN
OTBS
OO
MeO
MeO
OO
Cu1,3-dinitrobenzene
OTBS
O
O
MeO
MeO
O
O
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
O
O
R2
R1
MeO
R3
R4
R5
O
Ar
O
HO
Ar
O
HAr
In
O
Ar
OO
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 CHO
Br
In2Br3
3a.
b. TBSOTf
OO
MeO
Br OTBS
Br
MeO
OMe
OMe
a. tBuLib. CuCNc. O2
OO
MeO
OTBS
OMe
MeO OMe
a. 9-BBNb. H2O2, NaOHc. TBAFd. TEMPO, NCS
Eupomatilone 4
O
O
MeO
MeO
OMe
OMe
OO
19
Part E | Eupomatilones
Robert S. Coleman, J. Org. Chem. 2007, 72, 8724-8736
MeO CHO
Br
Eupomatilone 5
O
O
a. L-selectrideb. PhMgBrc. NaOH, H2O2
OH
OH
B BN
N N
NO
O
O
OB B CuCl, LiCl, KOAc
CO2Me
OAc
O
O B
MeO2C
Br O
O
MeO
OMe
MeO
OMe
MeO
100% ciser = 77:23
Pd2(dba)3S-PhosK3PO4
O
O
B(OH)2O
O
MeO
OMe
MeO
OO
O
O B
O
H
CO2Me
OMeOMe
OMe
Br
Transition State
20
Part E | (-)-Steganone
Gary A. Molander, J. Am. Chem. Soc. 2000, 122, 52-57
(-)-Steganone
O
O
O
O
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
O
O
MeO
MeO
MeO
O
(OC)3Cr
PCCNaOAc
O
O
O
O
MeO
MeO
MeO
O
O
O
O
O
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
Si
R1
R2 Cl*
sugar
Main Tools
Need to developed