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

Introduction

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).

18

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