Baran Group Meeting Limonoids 04/09/2011 · Hans Renata Limonoids Baran Group Meeting 04/09/2011...
15
Limonoids Hans Renata Baran Group Meeting 04/09/2011 Limonoid - "Characterized by a 4,4,8-trimethyl-17-furanylsteroid, wherein the four fused rings are designated A through D." Limonoids are tetranortriterpenoids. Triterpenes - 30 C atoms. "Tetranor" - 4 terminal Cs have been excised. Me Me Me Me Me O H 4 8 17 O Me O O O O O O O Me Me H Me H Limonin Different categories of limonoids A. Intact Limonoids Me Me Me Me Me O H O HO Me Me Me O AcO OH O HO OH AcO O O 'Protolimonoid' Toosendanin B. Degraded Limonoids O Me Me O O HO O Me HO Me O O O O Me Me O O OH HO 9-!-Hydroxyfraxinellone Dysodensiol A Dictamdiol B C. seco-Limonoids Me O O O O Me Me H Me H O A-seco: Tecleanin O Me O Me HO O Me Me O O O OH B-seco: Toonaciliatin B O O O Me Me Me HO O O Me Me Me OMe O C-seco: Desacetylsalannin O Me O O O O O O O Me Me H Me H A,D-seco: Jangomolide Biosynthesis Squalene R Me Me Me HO Me Me H Euphol/Tirucallol Limonoids Limonin, which lends its name to this family, is the bitter principle of citrus fruits and was the first of the limonoids to be isolated. [O] Harrison, Nat. Prod. Rep., 1988, 387 Ekong, Phytochemistry, 1985, 24, 2259 Ekong, Chem. Comm., 1971, 1117 H H H H H H H
Transcript of Baran Group Meeting Limonoids 04/09/2011 · Hans Renata Limonoids Baran Group Meeting 04/09/2011...
LimonoidsHans RenataBaran Group Meeting
04/09/2011
Limonoid - "Characterized by a 4,4,8-trimethyl-17-furanylsteroid, wherein the four fused rings are designated A through D."Limonoids are tetranortriterpenoids. Triterpenes - 30 C atoms. "Tetranor" - 4 terminal Cs have beenexcised.
Me
Me Me
Me Me
O
H4
8
17
O
Me
O
O
O
O
OO
O
MeMe H
MeH
Limonin
Different categories of limonoids
A. Intact Limonoids
Me
Me Me
Me Me
O
H
O
HO
Me
Me
Me
O
AcO
OH
O
HO
OH
AcO
O
O
'Protolimonoid' Toosendanin
B. Degraded Limonoids
O
Me
Me O
O
HO
O
MeHO
Me
OO
O
O
Me
Me
O
O
OH
HO
9-!-Hydroxyfraxinellone Dysodensiol A Dictamdiol B
C. seco-Limonoids
Me
O
O
O
OMe
Me H
MeH
O
A-seco: TecleaninO
MeO
MeHO
O
Me
MeO
O
O
OH
B-seco: Toonaciliatin B
O
O
OMe
Me Me
HO
O
O
Me
Me
Me
OMe
O
C-seco: Desacetylsalannin
O
Me
O
O
O
O
OO
O
MeMe H
MeH
A,D-seco: Jangomolide
Biosynthesis
Squalene
RMe
Me
Me
HOMeMe
H
Euphol/Tirucallol
Limonoids
Limonin, which lends its name to this family, is the bitter principle of citrus fruits and was the first of the limonoids to be isolated.
[O] Harrison, Nat. Prod. Rep., 1988, 387Ekong, Phytochemistry, 1985, 24, 2259Ekong, Chem. Comm., 1971, 1117
HH H
H
H
H H
Me
O
LimonoidsHans Renata
Baran Group Meeting04/09/2011
O
O
O
O
O
Me
HO
H
O
O
O
Me
MeHO
Me H
Trichilin B
O
O
O
O
O
OH
O
H
Me
O
MeO2C
Me
MeH
H
Me
Trijugin F
Me
O
O
O
OAcMe
H
AcO
HO
Me
OAc
OAc
O
AcO
MeO
O
O
O
O
Me
Chuktabrin B
O
Me
OHMe
Me
O
OH
O
O
O OMe
HO
HO
Khayanolide B
O
OO
Me
O
OO
O
O
Me
O
Me
H
Me
Me
Brownin F
N
O
O
O
Me
O
Me Me
O
Me
HOH
O
Me
HO
O
Me
HO
Me
Me
O
O
MeO
OOH
O
Xylogranatin F
Grandifotane A OO
HO
Me
H
OAcO
Me
HO
Me
O
O
OHC RO
H
Aphanamolide A
D. Highly Oxidatively Modified Limonoids
O
O
Me
Me
Me
O
OH
OH
HO
Me
H
O
Me
Me
MeO
O
Me
Me
O
HO
OH
Me
O
OH
MeMe
Entilin A
MeOH
O
O
O O
Me
MeO2C
AcO
O
OH
O
Me
Me
OOH
MeO2C
Azadirachtin
O
O
AcO
Me
Me
OAc
OH
MeO
O
O
OH
Tabularisin A
AcO
O
OAc
O
O
O
iPrO
LimonoidsHans Renata Baran Group Meeting04/09/2011
Degraded Limonoids - Synthesis of Fraxinellone Limonoid Family
O
Me
Me O
OCommon Approach
Diels-Alderor Robinson Annulation
Lithiofuran Addition
An Alternative Approach
MeMe OH
O
OPdII
Ar MeMe
tBuOO OtBuAr
Me
MeLnPd
O
Me
O
OtBu
O
Me
O
O
Me
O
O
Me
O
O
tBuO
MeHOH
O
O
Me
O
MeHOH
δ-Lactone Degraded Limonoids
OMe
MeO
O
OMe
O
O
Me MeO
CO2Me
OMe
H
O
Me
Me
O
Me
Me1. LTA2. K2CO3, MeOH
OH
O
OMe
MeOAc
O
OMe
MeOH
OMe
MeO
O
Pd(OAc)2, BQ,HOAc, MeCN
H2CrO4
60%2.6:1 anomers
Me2CO
62%
LDA, THF, -78 oC
62%,dr 2:1
Grubbs II
95%
305 oC
74%
1. LTA, 94%2. Ac2O, pyr
1. NBS, (PhCO)2O2
2. Li2CO3, DMF; H2O
3-Br-Furan, nBuLi
THF,-78 oC to rt
50%dr 7:3Fraxinellone
Morken, OL, 2005, 7, 5465
See:Tokoroyama, TL, 1972, 3401Tokoroyama, JCS Perkins 1, 1981, 1557Okamura; Nakatani, TL, 1997, 38, 263
Tokoroyama, TL, 1973, 49, 4869Grieco, JOC, 1985, 50, 1309
PyroangolensolideMethyl Angolensate
Taylor, Chem. Ind., 1970, 201
79%,3 steps
LimonoidsHans RenataBaran Group Meeting
04/09/2011
MeMe
O
Me
Me
Me
O
MeMe
O
Me
Me
Me
O
O
MeMe
O
Me
Me
O
OH
Me
Biomimetic Methyl Shift From Tetranortirucallane Terpenoid
H
H
HH H H
O
OAc
Me Me
HH
AcO
MeMe
O
OAcO
OAc
Me Me
HH
AcO
MeMe
AcO
Me
O
Me
O
OO
4N NaOH, 30% H2O2
tBuOH
40%
BF3.Et2O
Viability of Late Stage D-Ring Baeyer-Villiger Oxidation
Halsall, Chem. Comm., 1969, 242
MPP
Et2O
-3 oC
76%,2 steps
MeMe
AcO
Me
Me
H Me
H
O
R
MeMe
AcO
Me
Me
H Me
R
HCl
CHCl3
Note:
Halsall, JCS, 1956, 3172Barton, JCS, 1956, 4150
MeMe
AcO
Me
Me
Me R
H O
MeMe
AcO
Me
Me
Me R
H O
MeMe
AcO
Me
Me
Me R
H
MeMe
AcO
Me
Me R
Me
BF3.Et2O
C6H6
BF3.Et2O
C6H6
Halsall, Chem. Comm., 1969, 1493
Halsall, JCS (C), 1970, 1503
LimonoidsHans RenataBaran Group Meeting
04/09/2011
Me
HMeHO2C
CO2H
Agathic Acid Me
HMeMeO2C
Me
H
Me NOH
Me
HMeMeO2C
Me
H
Me
O
O
Me
HMeMeO2C
Me
H H
Me
O
O
Me
HMeMeO2C
Me
H
Me
O
O
MeMe
Me Me
H
H
CO2Me
O
ClHg
MeMe
Me Me
CO2Me
OR
MeMe
Me
H
H
OR
O
OMe
OH
MeMe
Me
H
H
OR
O
OMe
OHN
OH
MeMe
Me
H
HMe
OMOMO
OH
O
Me
HMeMeO2C
Me
H
O N
H
Me
Me
HMeMeO2C
Me
H
Me
O
O
AcO
MeMe
Me
H
H
OR
Me
OHOHO
O2N
Na O
MeMe
Me
H
H
O
Me
OHO
O
O
aq. NaOCl
CH2Cl20 oC
Hg(TFA)2,
MeNO2, -22 oC;
aq. NaCl
27-30%
1. HO3SONO,
pyr, 0 oC
2. h!, CH2Cl2,
50 oC
1. 1N HCl, MeCHO
2. Me4NBH(OAc)3,
Me2CO/HOAc
-78 oC
EtOH, reflux;
12N HCl-EtOH
(1:3), 10 oC
~28%
90%
1. 1M NaOEt, EtOH, 92%2. MOMBr, TBAI, DIPEA, MeCN, 92%
3. L-Selectride, THF, -78 oC
4. Mitsunobu
50%
2:1HOAc:H2SO4
PhMe,
75 oC
R = P(O)(OEt)2 R = P(O)(OEt)2
Corey's Synthesis of Azadiradione
Fernandez-Mateos, JCS Perkins 1, 1990, 2429Fernandez-Mateos, Tetrahedron, 1997, 53, 14131Fernandez-Mateos, Tetrahedron, 2005, 61, 8699
59%
93%
Construction of Azadiradione Skeleton
LimonoidsHans RenataBaran Group Meeting
04/09/2011
MeMe
Me
H
HMe
OMOMHO
OH
O
MeMe
Me
H
HMe
OMOMHO
OH
O
MeMe
Me
H
HMe
OMOMO
O
O
H H H
Me
MeMe
Me
H
HMe
OAcO
O
O
Me
MeMe
Me
H
HMe
HO
O
O
H
Me
See also:
Suarez's Synthesis of Limonin A-A' RIng System
Me
H
HMe
HO
C8H17
H
Me
O H
H
C8H17
H
MeO
O
MeO
Me
O
O
O
O
OO
O
MeMe H
MeH
Limonin
Me
O
O
O
MeMe H
H
H
H H
C8H17
ICH2I, Zn-Ag
Et2O
61%
1. DMP2. Li, NH33. DMP
92%,3 steps
LDA, THF, -78oC;
PhSeBr; H2O2,
H2O-pyr
then PGmanipulation
56% 13%
h!,Hg(OAc)2, I2, 10 atm O2
Azadiradione - Continued
Suarez, JOC, 1997, 62, 2975
Corey, JACS, 2008, 130, 6720
Corey, JACS, 1987, 109, 918Corey, TL, 1989, 30, 3023
LimonoidsHans RenataBaran Group Meeting
04/09/2011
O
Me
O
O
Me Me
O
CO2Me
O
Me
H
O
Me
O
O
Me Me
AcO
OAc
Me
O
Me
H O
O
Me
O
O
Me Me
AcO
OAc
Me
O
Me
H
7-Oxo-7-Deacetoxykhivorin
O
Me
O
O
Me
O
Me
H
O
OAc
AcO
MeMe
O
Me
O
O
Me Me
AcO
CO2Me
OAc
Me
H
O
Me
O
O
Me Me
HO
CO2Me
O
Me
H
Model Study Towards Ohchinolide and Nimbolidin
O
O
Me
O
Me
OR
AcO
AcO
Me
OMe
AcO
O
Me
Me
OR
AcO
AcO
Me
OMe
MeO2C
Ohchinolide Nimbolidin
AcOMe
H
Ph
OH
MeMeMe
O
Me
Me Ph
OHH
O
Me
Me
O
Me
O
Me
MeMe
Ph
AcO
MeMe
MeMe
PhMeO2C
CrCl2 MeCO3H
1. pTsOH2. (Methylation)
"Mild alkalinehydrolysis...followed byacidification" Jones
Methyl Angolensate
1. aq. KOH, EtOH
2. mCPBA
SOCl2, pyr,
CH2Cl2,
0 oC
59%
1. NaOMe, MeOH
2. Ac2O, DMAP, pyr
100%100%
Biomimetic Synthesis of Methyl Angolensate
Fernandez-Mateos, JOC, 2001, 66, 7632
Connolly, Chem. Comm., 1970, 1205See also: Ekong, JCS Perkins 1, 1972, 1943
LimonoidsHans RenataBaran Group Meeting
04/09/2011
Rearrangement in the Xylogranatin Series
O
O
Me
O
Me
MeOTig
OH
OAcOH
MeO2C
MeO
Xylogranatin A
O
O
Me
O
Me
MeOTig
O
OAcOH
MeO2C
MeO
O
O
Me
O
Me
Me
O
AcOOH
MeO2C
MeO
OO
O
O
MeMeO2C
Me
MeAcO
OH
Me
O
Xylogranatin B Xylogranatin C
Xylogranatin D
O
Me
O
O
Me Me
AcO
OAc
Me
O
Me
H O
7-Oxo-7-Deacetoxykhivorin
O
Me
O
O
Me
O
Me
H
O
OAc
AcO
MeMe
O
O
Me
O
O
Me Me CO2Me
Me
H
O
O
O
O
Me
O
O
Me Me CO2Me
Me
H
O
O
O
Me
O
O
Me
O
OMeO2C
H
Me
MeMexicanolide
MeCO3H
1. "Mild base"2. (Methylation)
3. SOCl24. Jones
CrCl2
aq. NaHCO3
CHCl3
5% HCl/Me2CO,reflux TEA
MeCN
(under N2)
140 oC
Biomimetic Synthesis of Mexicanolide
Connolly, Chem. Comm., 1971, 17Ekong, Chem. Comm., 1971, 727
Yue, OL, 2006, 8, 4935
LimonoidsHans RenataBaran Group Meeting
04/09/2011
O
OTBS
Me
O
CHO
O
OTBS
Me
OH
O
OTBS
Me
O
O
OOH
OH
Me
O
O
O
1. Ac2O, 92%
2. LDA, 69%
1. SOCl2, pyr, 72%
2. TBAF, 92%
Azedaralide
MeO
O
Me Me
H
O Me
OTBS
Me
MeMe
O
MeO
OMe
MeMe
O
MeO
O
OH
KH
C6H6
46%,22:78
syn:anti
Me
MeMe
OMe
MeO
OMeOTf
CH2Cl2
azedaralide, pTsOH
xylene, 180 oC
Me
O
O
O
O
Me Me
Me
H
CO2Me
Me
O
O
O
O
Me
Me Me CO2Me
Me
O
O
O
O
Me
Me Me CO2Me
Me
O
O
O
O
Me Me
Me
H
CO2Me
Me
O
O
O
O
Me Me
Me
H
CO2Me
20% 15% 4%
14%12%
TiCl4
47%
CH2Cl2, -78 oC
LDA
77%
Williams' Synthesis of Azedaralide and Cipadonoid B
Williams, Chem. Comm., 2011, 47, 2258
71%
Cipadonoid B
LimonoidsHans RenataBaran Group Meeting
04/09/2011
Me
O
OMe
Me H
MeH
O
H
OAcAcOO
O
Me
O
OMe
Me H
MeHO
O
H
OAcAcO
O
O
O
Me
Me
Dumsin Zumsin
Me
OAcH
Me
O
H
OAc
O
O
MeMe
HO
AcO
Walsuronoid A
HO
MeMe
OMOM
Me
OTBDPS
Me
MeMe H
Me
OTBDPS
O
MOMO
Me
MeMe H
Me
OTBDPS
OPiv
HO
MeMe H
H
HO
OPiv
Me
OTBDPS MOMO
HOHO
HOH
Me
OPiv
MeMe
OTBDPS
O
O
MOMO
HO
H
Me
OPiv
MeMe
OTBDPS
O
MeMe H
HO
MOMO
OPiv
Me
OTBDPS1. LTA, C6H6
2. Hg(TFA)2, H2O2
NaBH4,EtOH
KHMDS,THF
1. DIBAL-H2. PivCl, DMAP pyr, CH2Cl2
3. 9-BBNBr,
CH2Cl2, -40 oC
1. DMP, 89%
2. EtAlCl2, CH2Cl2 -78 oC, 40-68%
10 steps
Explanation for the relative stereochemistries of dumsin and zumsin
O
O
Me
HO
MeMe
Me
OH
O
Dumsin
Zumsin
(A)
(B)
B
A
44%
65%, 3 steps
14%,2 steps
92%
Paquette's Construction of ABC Ring System of Dumsin
Paquette, JOC, 2007, 72, 209
Kubo, J. Agric. Food Chem., 2002, 50, 5048
LimonoidsHans RenataBaran Group Meeting
04/09/2011
O
Me
O
O
Me Me
AcO
CO2Me
O
Me
H
O
O
AcO
O
MeO2CMe
Me
O
OAc
Me
Me
O
O
O
AcO
Me
Me
Me
Me
MeO2C O
O
Cipatrijugin A
Cipadesin D(Angolensate-type)
HO
O
O
OMe
O
MeMe
AcO
MeO2CMe
Me
O
AcO
OOMe
O
MeMe
AcO
MeO2CMe
Me
O
AcO
OHOH
O
O
Me
O
MeMe
MeAcO
Me
O
AcO
MeO2C
Cipadonoid DCipadonoid F
O
O
O
O
Me
Me
Me
O
O
MeO2C
HHO
Me
AcO
Trijugin A
O
O
O
O
Me
Me
Me
O
O
MeO2C
HHO
Me
O
O
O
O
O
O
Me
HO
H
O
O
O
Me
Me HOMe H
Trichilin B
Biosynthetic Diversification of Angolensate-Type Limonoids
Note: Oxidation states are treated loosely here and emphasis is given to bond connectivities
O
O
Me
Me
HOH
OAc
O
MeMe
MeO2C
O
O
Trichilin A
OH
O
O
Me
Me
Me
O
O
MeO2C
HO
Me
O
OH
OH
(A)
(B)
(C)
TL, 2009, 50, 2132Tetrahedron, 2009, 65, 7408OL, 2008, 10, 1905
Cipadonoid A
LimonoidsHans RenataBaran Group Meeting
04/09/2011
O
Me
O
O
Me
OAc
OMeO2C
H
Me
Me Mexicanolide-type
OH O
Me
O
O
Me
AcO
O
O
MeO2C
HO
HOH
OH
O
Me
HO
O
Me
HO
Me
MeO
O
MeO
OOH
O
O
Me
HO
O
Me
HO
Me
MeO
O
MeO
OOH
O
OH
Grandifotane A
O
Me
O
O
Me
OH
OMeO2C
H
Me
OH
OH
O
O
Me
OH
OH
OH
O
O
Me
MeO2C
OH
O
O
Me
OH
OH
OH
O
O
Me
MeO2C
OH
O
OH
O
Me
OH
OH
O
O
Me
MeO2C
O
OHO
O
Me
OH
OH
O
O
Me
MeO2C OHO
OH
O
Me
OH
OH
O
O
Me
MeO2CHO
O
OH
Khayanolide A
Khayanolide B
Me Me
MeMe
Note: Oxidation states are treated loosely here and emphasis is given to bond connectivities
Tetrahedron, 2001, 57, 119OL, 2010, 12, 252
Biosynthetic Diversification of Mexicanolide-Type Limonoids
OR
O
O
LimonoidsHans RenataBaran Group Meeting
04/09/2011
MeOH
O
O
O O
Me
MeO2C
AcO
O
OH
O
Me
Me
OOH
MeO2C
O
O
Me
OAc
Me
O
Me
Me MeH
H
HO
Me
OH
Me
O
Me
Me
H
OH
O
O
Nimbidinin
AcO
Me Me
Me
H
OR
O
Salannin
O
Me OMeO2C
AcO
Me Me
Me
H
OR
O
OH
Me OMeO2C HO
OH
O
Azadirachtin
O
O
tBuOO
PhS
O
tBuO
OO
H
SPh
O
PhS
OO
H
O O
Me Me
OH
SPh
OO
H
O O
Me Me
OO O
MeMe
PhS
OO
O O
MeMe
O
Model sequence to mimic the postulated biosynthesis of the eastern fragment of azadirachtin
Azadirachtin - Proposed Biosynthesis
[O]
LiHMDS,DMPU
THF
-78 oC
DIBAL TFA
Me2CO
1. NaIO4; TEA, toluene reflux
2. DMDO, Me2CO
65%,dr 2:1
68%,dr 3:1
69%, 2 steps
Winterfeldt, Chirality, 1997, 9, 454
Heasley, Eur. JOC, 2011, 19
+
OO
Me
AcO
MeOO
O
O
OH
O O
MeO2CH
H
Note the extensive hydrogen bonding network
Azadiradione
ODEIPS
OO
LimonoidsHans RenataBaran Group Meeting
04/09/2011
MeOH
O
O
O O
Me
MeO2C
AcO
O
OH
O
Me
Me
OOH
MeO2C
azadirachtin
OO
O O
O
O
OCO2Et
H
Me Me
OO
O
O
CO2Et
O
O
O
O
O
O
O
O
CO2Et
O O
MeMe
CHOPMBO
AsymmetricAllylation
OO
O
O
OO
OMe
H
ODEIPS
O O
CO2HO
O
OMe
OO
OOSiR3
PhMe, BHT,
200 oC,
sealed tube
43%,3:1 !:"
Nicolaou's Progress Towards Azadirachtin
LHMDS,
Me2SiCl2,
PhMe,
TEA
-78 to 70 oC
H
87%,dr 4:1
Proposed TS:
Establishing C8-C14 Connectivity - A Model System
Murai, OL, 2002, 4, 2877
Murai's Progress Towards Azadirachtin
OO
SEMO
SEMO
O
OHMeO2C
MeO
OPMB
OO
SEMO
SEMO
O
OMeO2C Br
MeO
OPMB
OO
SEMO
SEMO
O
OMeO2C
Me
O
OBzH
+
OO
SEMO
SEMO
OMeO2C
Me
O
O
OMe
H
H
Br2,76%
(Me3Si)3SiH, AIBN,42%
Nicolaou, ACIE, 2005, 44, 3447
Murai, TL, 1999, 40, 4387
LimonoidsHans RenataBaran Group Meeting
04/09/2011
MeOH
O
O
O O
Me
MeO2C
AcO
O
OH
O
Me
Me
OOH
MeO2C
Azadirachtin
S
S
O
O
O
OMe
OMe
PhMe2Si
CO2Me
O
O O
O
OMe
OMe
PhMe2SiMeO2C
H
O
O OH
S
S
MeO2CPhMe2Si
HO
H
OMeO2C
H
OTBS
O
OPhO
O
CN
OMeO2C
H
O
O
OPh
O
O
CN
OMeO2C
OOH
MeO2C
O
H
HO
HO
OMeO2C
OOBn
MeO2C
O
H
TESO
TESO
Me
OMeO2C
OOBn
MeO2C
O
H
TESO
TESO
Me
OO
OPMB
OBn
OMeO
MeO2C
OOBn
MeO2C
O
H
TESO
TESOO
O
OBn
OPMB
OMe
1. Tebbe
2. DIPEA,
hydroquinone
toluene, 85 oC
57%,2 steps
pTsOH
aq. MeCN
55 oC
63%
1. TBAF2. PDC
3. DBU, MeCN
85%
1. DMDO2. MeOH, TEA
3. CH2N24. HCl (cat.), MeCN
OO
OPMB
OBn
OMe
MsO
NaH, 15-crown-5,
THF, 0 oC
1. TBAF
2. oDCB, 185 oC,
or [(PH3PAu)3O]BF4
Ley, ACIE, 2007, 46, 1
Ley's Total Synthesis of Azadirachtin
(Deoxygenative Radical Cyclization,Epoxidation, PG Removal)
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