Literature ReportLiterature Report
Total Synthesis of LimoninTotal Synthesis of Limonin
Reporter: Mu-Wang Chen Checker: Yue JiChecker: Yue Ji
Date: 2015-07-07
Y hit S t lYamashita, S. et al.Tohoku University
Angew. Chem. Int. Ed. 2015, 54, 8538–8541.
1
Contents
1 Introduction
2
3
Brief retrosynthetic analysis of limonin (1)
Total synthesis of limonin (1)3
4
Total synthesis of limonin (1)
Total synthesis of limonoid (2)
Summary5
Introduction
O
O
E
OO
O
A
313
17
DC
O O
O
HO
A'1
4
8B
OH
limonin (1)
first isolated from citrus fruit in 1841the structure of 1 remained unknown until 1960first total synthesis of (±)-limonin 1 in 2015first total synthesis of (±) limonin 1 in 2015抗肿瘤、镇痛抗炎、防虫杀虫、抗氧化活性、抗菌性、抑
制 HIV、降低胆固醇、明显的利尿作用、改善心脑血管循环及改善睡眠、抗病毒、调节细胞色素等
3
及改善睡眠、抗病毒、调节细胞色素等
Brief retrosynthetic analysis of limonin (1)
5Yamashita, S. et al. Angew. Chem. Int. Ed. 2015, 54, x–x
Construction of the limonoid framework
a) PCl3, DMF, THF, RTc) TMS CH3
TMS
n BuLi THFOH
geraniol (4)
a) PCl3, DMF, THF, RT
b) m-CPBA, K2CO3, DCMCl
4'O
d) Al(Oi-Pr)3, Toluene
5
HO
75% yield
n-BuLi, THF
a) SOCl Et O
TMS
EtOTBAF THF
H
EtOMn(OAc)3 2H2Oa) SOCl2, Et2O
b) NaH, n-BuLiDMPU, THF
O O
OEt
Cl 69% yieldO
OCl
6
TBAF, THF
98%
O
OCl
7
d.r. = 2.1:1 for C1364%
Mn(OAc)3 2H2O
6 7
H 8
D
H
O
C
B
EtO2CCl 13
3
EtO2CMeI t BuOK t BuOH
EtO2C
LiAlH THF
H H
8O
62% yield
MeI, t-BuOK, t-BuOH
80%H H
9O
LiAlH4, THF
97%
HO TBSO
H H
9'HO
a) TBSCl, NaH, THF, 75%
b) Ac2O, pyridine, DMAPDCM, quant.
H H
11AcO
9' 11
TBSOO
m-CPBA, NaHCO3, DCM
63% H H
AcO
TBSO
12
O O
H H
O
Oa) LiAlH(Ot-Bu)3, THF
b) TESOTf 2 6-lutidine DCM H H
O
O
LiHMDS, TMSCl, Et3N, THF
Pd(OAc)2 MeCN 92%
2
OH
HOb) TESOTf, 2,6 lutidine, DCM H H
15
OTESH
TESO
O
7
(84%, d.r. = 4.6:1)
Pd(OAc)2, MeCN, 92%
O O
O
a) Tf O DTBMP DCMO O
H H
16
OTESH
TESO
Oa) Tf2O, DTBMP, DCM
b) 17, Pd(PPh3)4, CuCl, LiClDMSO
H
18OTES
HTESO
O83% Bu3Sn
17
O O O O
H
18OTES
HTESO
O
O2 (1 atm), methylene blueNaHCO3, DCM, hv (sunlamp)
92% H
18'OTES
HTESO
O
O
O
DIBAL, DCM
Ac2O, DMAP, 80%
O O
O
H
19OTES
HTESO
O
O
O(Ph3P)3RuCl2, DCM
H
20OTES
HTESO
O OSiO2
19 20O
R4
17 O
H
21OTES
HTESO
O O21 R4 = -H
21 : R4 = -HDBU, Toluene61% (2 steps)
21 /21 : 5.4:1
O
O O
H
OTESTESO
O O
H17 O
HO
O
OO
a) H2O2/urea, aq NaOHMeOH, DME
b) TBAF, THF
PhI(OAc)2, I2, O2 (1 atm)cyclohexane, CCl4, hvD
3OTES
HTESO
21 : R4 = -H
OTESH
HO49%
22
O O
4
O
O
O3 OO
O
O
Aa) TBAF, THF OO
O
OO
HO
OTESH
OO
23
D
H
4O O
OTESH
HO
A'
24
Ab) TPAP, NMO
DCM, 4Å MS O O
OH
HO
limonin (1)
17%(3 steps)
1
23
Simple enantioselective approach to synthetic limonoids
O
TBS
+
SLi
O
O
Ph
THF, 94%
OTBS
O3
+
4O
5
MeAlCl2, DCM
O
H DIBALH, n-BuLi H
OH
then NaOEt, EtOH
6TBSO
H43% THF, 88%7
TBSOH
Corey, E. J. et al. J. Am. Chem. Soc. 2008, 130, 6720-6721.
OH
n-BuLi, -25 oCthen CS2, 0 oC
OR
7TBSO
H
H
then MeI, 0 oC95%
8TBSO
H
H R = C(S)SMe
H X
a) AIBN, Bu3SnH, Toluene
b) O3, DCM, MeOH, -78 oCthen P(OEt)3, 76% TBSO
H
H
H
9a X = CHEt9b X = O
O OTf
H
H
H
O
a) KOt-Bu, t-BuOH/t-amyl alcoholthen MeI, 0 to 4 oC, 89%
b) KHMDS THF 78 t 30 oC H H
OTf
TBSO
H
H
H
9
b) KHMDS, THF, -78 to - 30 oCthen PhNTf2, - 30 oC, 90% TBSO
H
H
H
10
O
Pd(PPh3)4, CuCl, LiCl, DMSO
O
Bu3Sn
TBSO
H
H
H
11
85%
11
Summary
Yamashita’s group: 35 steps
key steps: Tandem radical cyclizationRobinson annulationBaeyer Villiger oxidationBaeyer–Villiger oxidationSuárez reaction
Corey’s group: 13 stepsCorey s group: 13 steps
key steps: Tandem radical cyclizationy p yStille coupling
17
Limonin (1), the flagship congener of the limonoids,was first isolated in1841 during studies on the bitter components of the citrus fruit. However,the structure of 1 remained unknown until 1960, when a historiccollaboration between the Arigoni, Barton, Corey, Jeger, and Robertsongroups led to the determination of the exact structure of 1 by chemicald i ti ti d X diff ti th d Si th l h d dderivatization and X-ray diffraction methods. Since then, several hundredlimonoids have been isolated. The intact limonoid framework ischaracterized by a 4,4,8-trimethyl-17-furyl-13 α-androstane, but this familyencompasses a diverse array of structural architectures as a result ofencompasses a diverse array of structural architectures as a result ofoxidations and skeletal rearrangements. Not surprisingly, the uniquearchitectures and the wide spectrum of biological properties of limonoidshave attracted keen interest from the synthesis community and for examplehave attracted keen interest from the synthesis community, and for example,azadiradione, cipadonoid, mexicanolides, and azadirachtin have beensynthesized. Herein, we describe the first total synthesis of (±)-limonin (1).
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In summary, we have achieved the first total synthesis of (±)-limonin (1)in 35 steps from geraniol (4). Our synthesis features 1) the efficientconstruction of the limonoid androstane framework with C13αco s uc o o e o o d a d os a e a e o C 3αconfiguration by a tandem radical cyclization and subsequent Robinsonannulation (7→3→9), 2) a ketone formation from the hindered exomethylene group, possibly through epoxidation and nitrile additiony g p p y g pfollowed by MeCN elimination (11→13), 3) the installation of anepoxylactone moiety by singlet-oxygen cycloaddition, ruthenium-catalyzed bis(epoxide) formation, and Baeyer–Villiger oxidation (18→22),and 4) a Suárez reaction to construct the unique AA’ ring system from thehemiacetal (22→24). We believe that the synthetic strategy developedhere will allow for the synthesis of diverse limonoid architectures.
19