Limonoids

Hans Renata
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.
17
O
Me
Me Me
H
Limonoids
H
O
Me
H
H
Squalene
Me
O
Me
H
4
Me R
Me
O
Me
8
Biosynthesis
O
O
Me
Baran Group Meeting
04/09/2011
Limonoids
HO
Me
O
O
Me
[O]
Me
Euphol/Tirucallol
O
Harrison, Nat. Prod. Rep., 1988, 387
Ekong, Phytochemistry, 1985, 24, 2259
Ekong, Chem. Comm., 1971, 1117
Me H Limonin
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.
Different categories of limonoids
C. seco-Limonoids
A. Intact Limonoids
O
O
AcO
Me
O
OH
Me
Me
H
O
H
Me Me
O
O
Me
Me
HO
Toosendanin
HO
O
9-!-Hydroxyfraxinellone
Me
Me
O
Me
O
O
O
Me
Me
Dysodensiol A
O
Me
OH
Dictamdiol B
O
O
Me
Me
O
Me
HO
O
B-seco: Toonaciliatin B
O
O
Me
O
C-seco: Desacetylsalannin
O
Me
H
Me H
O
Me
H
O
O
H
OMe
HO
HO
Me
O
O
Me
O
O
A-seco: Tecleanin
O
Me
O
Me
O
Me H
Me
O
Me OH
H
B. Degraded Limonoids
O
O
Me
Me
O
OH
'Protolimonoid'
Me
H
H
AcO
HO
HO
O
Me
Me
O
O
O
O
O
A,D-seco: Jangomolide
O
Hans Renata
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Limonoids
D. Highly Oxidatively Modified Limonoids
O
O
HO
Me
Me
O
AcO
Me
OO
H
H
HO
H
Me
Me
OO
Trichilin B
Me
O
H
OAc
O
H
MeO
O
O
O
O
O
Me
OAc
OAc
O
Me
O Trijugin F
MeO2C
Me
AcO
O
H
Me
O
O
O
HO
OH
O
O
Me
O
O
O
O
Me
Me
OH
Chuktabrin B
Khayanolide B
HO
O
O
Me
Me
O
Me H
Me
O
Me
O
O
O
O
O
Me
O
Xylogranatin F
H
Me Me
Me
OH
Me
Me
HO
H
O O
OH
Me
Me
HO
Me
O
O
AcO
HO
RO
O
Me
Me
H
O
O
O
HO O
H
HO
O
Me
O
Aphanamolide A
O
O
Me
Me
OH
OH
Me
Me
Entilin A
Me
Grandifotane A
O
OH
OHC
O
HO
O
Me
Me
Me
O
O
OH
MeO
Me
O
Brownin F
O
N
O
O
Me
O O
Me
AcO
MeO2C
AcO
MeO2C
OH
O
O
O
Me
Me
O
O
Me
O
OH
Me
HO
O
Me
OMe
Me
O
O
OH
AcO Me
MeO
OH
O
Azadirachtin
O
Me
O
O
O
O
Me
OH O OAc
O
OH
iPr
OAc O
Tabularisin A
Hans Renata
Baran Group Meeting
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Limonoids
Degraded Limonoids - Synthesis of Fraxinellone Limonoid Family
δ-Lactone Degraded Limonoids
Common Approach
O
O
O
Lithiofuran Addition
Me
O
Diels-Alder
or Robinson Annulation
Me
Me
305 oC
Me
O
Me
O
See:
Tokoroyama, TL, 1972, 3401
Tokoroyama, JCS Perkins 1, 1981, 1557
Okamura; Nakatani, TL, 1997, 38, 263
O
O
O
H
O
O
Me
Me Me CO2Me
Pyroangolensolide
Methyl Angolensate
An Alternative Approach
Taylor, Chem. Ind., 1970, 201
O
Pd(OAc)2, BQ,
HOAc, MeCN
tBuO
O
tBuO
OH 2.6:160%
anomers
Me
Ar Me
LnPd
Me
PdII
Ar
Me
1. LTA
2. K2CO3,
MeOH
Me
Me
Me
O
Me OH
O
OtBu
H2CrO4
Me
OAc
O
74%
O
Me
LDA, THF, -78 oC
O
Me
O
Me
O
1. LTA, 94%
2. Ac2O, pyr
Me
O
Me
Me
O
O
O
Me2CO
62%
OtBu
79%,
3 steps
Me
Fraxinellone
H
HO Me O
Me
3-Br-Furan, nBuLi
O
Me
O
2. Li2CO3, DMF;
H2O
O
Grubbs II
O
1. NBS,
(PhCO)2O2
O
O
Me
62%,
dr 2:1
OH
O
Me
THF,
-78 oC to rt
50%
dr 7:3
O
Me
O
95%
HO Me
H
O
Morken, OL, 2005, 7, 5465
Tokoroyama, TL, 1973, 49, 4869
Grieco, JOC, 1985, 50, 1309
Hans Renata
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Limonoids
Biomimetic Methyl Shift From Tetranortirucallane Terpenoid
O
O
Note:
O
Me R
Me
Me
BF3.Et2O
MPP
Me
H
Me
H
Et2O
-3 oC
Me
O
H
Me
H
O
Me
H
H
Me
HCl
O
Me
OH
H
CHCl3
AcO
O
Me Me
H
Me
H
76%,
2 steps
Me
O
Me Me
Me R
Me
Me Me
Me Me
Me
AcO
Me Me
Halsall, JCS, 1956, 3172
Barton, JCS, 1956, 4150
Halsall, Chem. Comm., 1969, 242
Me R
Me R
BF3.Et2O
Me
H
Me
Me R
Me
H
C6H6
AcO
Me Me
O
Me
H
AcO
Me Me
Me Me
Viability of Late Stage D-Ring Baeyer-Villiger Oxidation
O
O
Me
Me
4N NaOH, 30% H2O2
Me
Me
AcO
O
Me
O
Me
tBuOH
H
AcO
H
O
OAc
Me Me
Halsall, Chem. Comm., 1969, 1493
H
40%
AcO
H
O
OAc
Me Me
O
Me
Me
C6H6
AcO
Halsall, JCS (C), 1970, 1503
AcO
BF3.Et2O
Me
AcO
Me R
O
Me Me
Me
Hans Renata
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Limonoids
Construction of Azadiradione Skeleton
Me
Me
H
MeO2C Me
CO2H
Me
Me
Agathic Acid
Me
Me
AcO
Me
H
Me
O
Me
H
H
MeO2C Me
93%
Fernandez-Mateos, Tetrahedron, 1997, 53, 14131
Fernandez-Mateos, Tetrahedron, 2005, 61, 8699
O
N
Me
H
CH2Cl2
0 oC
O
H
MeO2C Me
O
H
Me
H
O
H
MeO2C Me
aq. NaOCl
H
Fernandez-Mateos, JCS Perkins 1, 1990, 2429 MeO2C Me
Me
H
NOH
Me
Me
Me
H
59%
H
HO2C Me
Me
PhMe,
75 oC
O
O
Me
2:1
HOAc:H2SO4
Me
H
Me
O
O
H
MeO2C Me
Corey's Synthesis of Azadiradione
Hg(TFA)2,
MeNO2, -22 oC;
aq. NaCl
OR
Me
Me
O
Me
CO2Me
Me Me
ClHg
R = P(O)(OEt)2
2. Me4NBH(OAc)3,
Me2CO/HOAc
-78 oC
Me
Me
H
O
Me
CO2Me
O
H
Me Me
Me
H
O
1. HO3SONO,
pyr, 0 oC
OH
H
Me Me
Na
H
Me Me
O
2. h!, CH2Cl2,
50 oC
O
Me
90%
H
O
Me
O
H
Me Me
N
OH
OH
1. 1M NaOEt, EtOH, 92%
2. MOMBr, TBAI,
DIPEA, MeCN, 92%
Me
H
EtOH, reflux;
12N HCl-EtOH
(1:3), 10 oC
Me
O
O
O2N
OH
OH
Me
~28%
R = P(O)(OEt)2
OR
1. 1N HCl,
MeCHO
Me
H
27-30%
OR
OR
O
H
Me Me
OH
O
3. L-Selectride, THF, -78 oC
4. Mitsunobu
OH
H
O
50%
Me
H
Me Me
OMOM
Hans Renata
Baran Group Meeting
04/09/2011
Limonoids
Azadiradione - Continued
O
Me
Me
H
HO
O
OH
Me
Me
H
61%
OMOM
H
Me Me
ICH2I, Zn-Ag
HO
Me
92%,
3 steps
OMOM
H
Me Me
LDA, THF,
PhSeBr; H2O2,
H2O-pyr
Me
OH
H
O
-78oC;
1. DMP
2. Li, NH3
3. DMP
Et2O
H
O
Me
H
O
H
Me Me
O
H
Me
then PG
manipulation
OMOM
Me
O
H
O
O
See also:
Me
OAc
H
Me Me
Corey, JACS, 1987, 109, 918
Corey, TL, 1989, 30, 3023
Me
Me
Me
H
HO
O
H
H
Me Me Corey, JACS, 2008, 130, 6720
Suarez's Synthesis of Limonin A-A' RIng System
O
Me C8H17
h!,Hg(OAc)2,
I2, 10 atm O2
O
HO
H
Me Me
H
H
Me C8H17
O
O
O
Me C8H17
O
O
H
O
Me
Me
O
Me H
H
H
H
Me
H
56%
13%
H
O
Me
O
Me
H
Me H
H
O
O
O
Limonin
Suarez, JOC, 1997, 62, 2975
Hans Renata
Baran Group Meeting
04/09/2011
Limonoids
Model Study Towards Ohchinolide and Nimbolidin
O
MeO2C
AcO
Me
O
AcO
Me
Me
AcO
Me
O
O
Me
AcO
Me
Me
O
Me Ph
1. aq. KOH,
EtOH
Me
Me
2. mCPBA
H
OH
O
O
Nimbolidin
O
AcO
O
1. NaOMe, MeOH
Ph
Me
Me
CH2Cl2,
0 oC
OH
Me
O
Ohchinolide
SOCl2, pyr,
H
100%
Me
Me Ph
Me
ORMe
AcO
ORMe
AcO
Me
2. Ac2O, DMAP,
pyr
Me
Me
MeO2C
Me
Me
100%
59%
Ph
Me
Fernandez-Mateos, JOC, 2001, 66, 7632
Biomimetic Synthesis of Methyl Angolensate
O
Me
OAc
Me
H
AcO
O
OAc
Me
O
O
H
O
AcO
Me Me
OAc
Me
MeCO3H
O
Me
H
AcO
Me
O
Me Me
H
O
AcO
Me Me CO2Me
O
O
H
O
Me Me CO2Me
O
O
Me
O
Me
Jones
O
HO
O
OAc
Me
O
Me
H
Me
1. pTsOH
2. (Methylation)
O
O
O
O
Me
Me
Me
7-Oxo-7-Deacetoxykhivorin
"Mild alkaline
hydrolysis...
followed by
acidification"
O
Me
Me
CrCl2
O
Me
O
O
O
Methyl Angolensate
Me Me CO2Me
Connolly, Chem. Comm., 1970, 1205
See also: Ekong, JCS Perkins 1, 1972, 1943
Hans Renata
Baran Group Meeting
04/09/2011
Limonoids
Biomimetic Synthesis of Mexicanolide
O
O
Me
Me
OAc
Me
H
O
O
AcO
OAc
Me
MeCO3H
O
Me
O
H
AcO
Me
O
Me Me
O
Me
1. "Mild base"
2. (Methylation)
O
Me
H
4. Jones
Me
CrCl2
O
O
Me
O 3. SOCl2
O
O
O
O
O
O
Me Me CO2Me
O
O
H
O
Me
O
O
Me
Me Me CO2Me
7-Oxo-7-Deacetoxykhivorin
Me
aq. NaHCO3
Me
CHCl3
O
H
O
MeO2C
Me
Me
O
O
Connolly, Chem. Comm., 1971, 17
Ekong, Chem. Comm., 1971, 727
Mexicanolide
Rearrangement in the Xylogranatin Series
MeO2C
Me
O
MeO2C
OH
Me
Me
Me
OH
OTig OAc
Xylogranatin A
O
Me
O
5% HCl/Me2CO,
reflux
MeO2C
O
Me
Me
Me
O
O
OH
OTig OAc
Xylogranatin B
O
O
Me
O
O
TEA
MeCN
O
Me
Me
Me
AcO
OH
Xylogranatin C
O
O
O
O
(under N2)
140 oC
MeO2C
Me
O
Me
Me
OH
O
AcO
Me
O
O
Xylogranatin D
Yue, OL, 2006, 8, 4935
Hans Renata
Baran Group Meeting
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Limonoids
Williams' Synthesis of Azedaralide and Cipadonoid B
CHO
O
O
LDA
Me
1. Ac2O,
92%
Me
O
Me
O
O
2. LDA,
69%
77%
O
OTBS
1. SOCl2,
pyr, 72%
Me
OH
O
O
O
OH
OTBS
2. TBAF,
92%
O
OTBS
OH
Azedaralide
TiCl4
OTBS
O
O
O
Me
MeO
H
Me
O
CH2Cl2, -78 oC
Me Me
O
C6H6
OH
Me Me
47%
Me
O
KH
MeO
OMe
CH2Cl2
MeO
Me Me
46%,
22:78
syn:anti
azedaralide, pTsOH
Me
O
MeOTf
xylene, 180 oC
MeO
Me Me
71%
O
O
O
Me
O
Me
O
Me
H
Me Me CO2Me
O
O
O
H
Me Me CO2Me
O
O
15%
Me
O
O
Me
H
O
O
O
O
O
O
Me
Me
Me Me CO2Me
Cipadonoid B
20%
Me
Me
O
Me
O
4%
Me Me CO2Me
12%
Me Me CO2Me
14%
Williams, Chem. Comm., 2011, 47, 2258
Hans Renata
Baran Group Meeting
04/09/2011
Limonoids
Paquette's Construction of ABC Ring System of Dumsin
Explanation for the relative stereochemistries of dumsin and zumsin
O
AcO
O AcO
O
Me
HO
Me
O
H
O
Me H
OAc
Me
O
H
Me
Me
O
Me
Dumsin
AcO
Me H
OAc
O
O
O
Me
O
Zumsin
Me
Me
(B)
O
A
Dumsin
O
HO
H
H
Me
OH
Me
Me
HO
Me
H
O
O
O
O
OAc
Me
Me (A)
Me
OAc
B
Walsuronoid A
Zumsin
Kubo, J. Agric. Food Chem., 2002, 50, 5048
Me
MOMO
Me
OMOM
HO
OTBDPS
KHMDS,
THF
44%
Me
Me
OTBDPS
Me H
OTBDPS
3. 9-BBNBr,
CH2Cl2, -40 oC
MOMO
Me
HO
HO
Me
OPiv
HO
Me
OPiv
2. Hg(TFA)2,
H2O2
H
Me
Me
Me
Me
65%, 3 steps
1. LTA,
C6H6
10 steps
H
Me
MOMO
OTBDPS
MeH
O
14%,
2 steps
1. DMP, 89%
2. EtAlCl2, CH2Cl2
-78 oC, 40-68%
OTBDPS
Me
Me
HO
HO
1. DIBAL-H
2. PivCl, DMAP
pyr, CH2Cl2
OTBDPS
HO
O
Me
O
Me
MeH
H
Me
OPiv
NaBH4,
EtOH
92%
OPiv
OTBDPS
MOMO
HO
Me
O
Me
Me H
OPiv
Paquette, JOC, 2007, 72, 209
Hans Renata
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Limonoids
Biosynthetic Diversification of Angolensate-Type Limonoids
O
O
O
AcO
Me
O
Me
O
O
Me
O
O
H
Me
MeO2C
Me
AcO
O
MeO2C
O
O
Me
AcO
Me Me CO2Me
H
O
Me
HO
O
Me
HO
O
Me
Me
MeO2C
O
O
Me
H
Me
O
O
O
O
Me
O
Cipatrijugin A
Me
O
Trijugin A
Trichilin A
(A)
Cipadesin D
(Angolensate-type)
O
O
Me
AcO
O
HO
O
O
MeO2C
Me
TL, 2009, 50, 2132
Tetrahedron, 2009, 65, 7408
OL, 2008, 10, 1905
OO
H
Me
Me
H OH
H
HO
Me
OO
OAc
(B)
OH
O
Me
O
OH
O
Me
O
O
Trichilin B
Me
O
MeO2C
Me
O
Me
Me
Me
O
O
HO
(C)
O
O
Me
AcO
O
O
HO
O
O
H
Me
MeO2C
Me
Me
MeO2C
OAc
AcO
Me
O
O
AcO
Me
Me
O
MeO2C
Me
O
O
Cipadonoid F
Me Me
Cipadonoid A
Note: Oxidation states are treated loosely here and emphasis is given to bond connectivities
Me
AcO
Me
O
OH
MeO2C
Me
Me
Me
Me
OH
AcO
O
O
O
AcO
Me
Me
O
O
O
Me
Cipadonoid D
Hans Renata
Baran Group Meeting
04/09/2011
Limonoids
Biosynthetic Diversification of Mexicanolide-Type Limonoids
O
O
Me
OH Me
Me
O
H
Me H
O
MeO2C
Me
Me
HO
O
O
O
MeO2C
OAc
O
OH
O
O
O
OH
HO
O
HO
O
Me
H
O
O
OH
O
OH
MeO2C
O
OH
O
O
Me
O
Me
O
O
MeO2C
Me
Me
OH
O
O
HO
OH
OH
O
Me
OH
OH
MeO2C
OH
OH
O
Me
O
Me
Me
OH
O
O
Me
MeO2C
O
HO
Grandifotane A
O
OH Me
O
AcO
O
HO
Me
O
O
Mexicanolide-type
Me
Me
MeO
Me
O
OH
Me
OH
Me
Me
MeO
Me
O
O
OH
O
OH
OH
Khayanolide A
O
O
Me
Tetrahedron, 2001, 57, 119
OL, 2010, 12, 252
OH
Me
OH
OH
O
MeO2C
HO
O
Me
OH
Note: Oxidation states are treated loosely here and emphasis is given to bond connectivities
Me
O
MeO2C
HO
O
OH
Me
Khayanolide B
O
Me
OH
O
Hans Renata
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Limonoids
Azadirachtin - Proposed Biosynthesis
O
O
O
Me
[O]
Me
Me
OH
Me
O
Me Me
HO
OAc
O
Me
AcO
MeO2C
MeO
O
O
MeO2C
H
O O
O
Me O
Note the extensive hydrogen bonding network
O
OH
AcO
OH
O
Me
OH OH
Salannin
MeO2C
OH
O
O
O
Me
Me
AcO
O
Nimbidinin
Me
O
Me
H
AcO
O
Azadiradione
Me
Me
Me HO
O
OH
Me
O
MeO2C
OR
Me
O
Me
H
H
Me
H
H
O
MeO2C
OR
Me
Me
O
OR H O
O
H O
Azadirachtin
O
Heasley, Eur. JOC, 2011, 19
Model sequence to mimic the postulated biosynthesis of the eastern fragment of azadirachtin
O
O
tBuO
O
THF
-78 oC
tBuO H
O
65%,
dr 2:1
1. NaIO4;
TEA, toluene
reflux
PhS
O
O O
Me
O
SPh
O
Me
69%, 2 steps
PhS
O
O
SPh
H
O
O
Me Me
DIBAL
O
H
O
O
O
TFA
Me2CO
68%,
dr 3:1
O
O
2. DMDO, Me2CO
OH
Me Me
LiHMDS,
DMPU
PhS
+
O
O
O
O O
Me
Me
Winterfeldt, Chirality, 1997, 9, 454
Hans Renata
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Limonoids
Murai's Progress Towards Azadirachtin
Asymmetric
Allylation
PMBO
O
CHO
O
O
PhMe, BHT,
200 oC,
sealed tube
O
O
O
O
O
O
O
CO2Et
O O
Me
O
Me
Murai, TL, 1999, 40, 4387
O
SEMO
OMe
O
H
O
ODEIPS
SEMO
MeO2C
Proposed TS:
O
O
azadirachtin
(Me3Si)3SiH, AIBN,
42%
O
OSiR3
SEMO
O
O
O
SEMO
MeO2C
O
ODEIPS
O
H
O
MeO
O
Br
O
Me H
O
O
SEMO
SEMO
MeO2C
O
OMe
CO2H
Br2,
76%
O
O
OMe
SEMO
O
OPMB
O
O
Me
H
H
Murai, OL, 2002, 4, 2877
Nicolaou, ACIE, 2005, 44, 3447
O
OH
OH
OPMB
OH
O
Me
AcO
MeO2C
O
87%,
dr 4:1
O
O
MeO2C
OH
O
O
O
Me
+ MeO
O
LHMDS,
Me2SiCl2,
PhMe,
TEA
-78 to 70 oC
O
Me
Me
Nicolaou's Progress Towards Azadirachtin
Establishing C8-C14 Connectivity - A Model System
O
H
43%,
3:1 !:"
O
O
O
CO2Et
O
O
CO2Et
Me Me
O
O
O
O
O
O
O
SEMO
MeO2C
O
O
OBz
Hans Renata
Baran Group Meeting
04/09/2011
Limonoids
Ley's Total Synthesis of Azadirachtin
O
OMe
1. Tebbe
2. DIPEA,
OMe hydroquinone
S
toluene, 85 oC
O
O
OMe
H
PhMe2Si
O
S
PhMe2Si
MeO2C
57%,
2 steps
HO
pTsOH
O
O
OH
O
OMe
Ph
S
H
aq. MeCN
PhMe2Si
55 oC
MeO2C
O
O
63%
CO2Me
O
O
CN
O
Ph
O
H
O
MeO2C
MeO2C
OH
O
HO
1. DMDO
2. MeOH, TEA
CN 2. PDC
O
H
OTBS
S
MeO2C
H
HO
MeO2C
O
MeO2C
OBn
O
TESO
H
TESO
MeO2C
O
O
MsO
O
O
TESO
MeO2C
O
O
O
MeO2C
OBn
O
TESO
OMe
(Deoxygenative Radical Cyclization,
Epoxidation, PG Removal)
OPMB
TESO
MeO2C
O
O
OBn
O
O
OMe
O
Me
MeO2C
OH
O
O
O
Me
Me
Ley, ACIE, 2007, 46, 1
OMe
THF, 0 oC
O
H
O
85%
O
H
1. TBAF
2. oDCB, 185 oC,
or [(PH3PAu)3O]BF4
OPMB
OBn
Me
MeO2C
OBn
O
TESO
O
3. DBU,
MeCN
OPMB
OBn
Me
3. CH2N2
4. HCl (cat.),
MeCN
1. TBAF
O
NaH, 15-crown-5,
O
O
AcO
MeO2C
Me
O
O
OH
OH
O
Azadirachtin